Showing papers in "Annual Review of Neuroscience in 2012"

The attention system of the human brain: 20 years after.

Abstract: Here, we update our 1990 Annual Review of Neuroscience article, “The Attention System of the Human Brain.” The framework presented in the original article has helped to integrate behavioral, systems, cellular, and molecular approaches to common problems in attention research. Our framework has been both elaborated and expanded in subsequent years. Research on orienting and executive functions has supported the addition of new networks of brain regions. Developmental studies have shown important changes in control systems between infancy and childhood. In some cases, evidence has supported the role of specific genetic variations, often in conjunction with experience, that account for some of the individual differences in the efficiency of attentional networks. The findings have led to increased understanding of aspects of pathology and to some new interventions.

Mechanisms of Gamma Oscillations

Abstract: Gamma rhythms are commonly observed in many brain regions during both waking and sleep states, yet their functions and mechanisms remain a matter of debate. Here we review the cellular and synaptic mechanisms underlying gamma oscillations and outline empirical questions and controversial conceptual issues. Our main points are as follows: First, gamma-band rhythmogenesis is inextricably tied to perisomatic inhibition. Second, gamma oscillations are short-lived and typically emerge from the coordinated interaction of excitation and inhibition, which can be detected as local field potentials. Third, gamma rhythm typically concurs with irregular firing of single neurons, and the network frequency of gamma oscillations varies extensively depending on the underlying mechanism. To document gamma oscillations, efforts should be made to distinguish them from mere increases of gamma-band power and/or increased spiking activity. Fourth, the magnitude of gamma oscillation is modulated by slower rhythms. Such cross-frequency coupling may serve to couple active patches of cortical circuits. Because of their ubiquitous nature and strong correlation with the "operational modes" of local circuits, gamma oscillations continue to provide important clues about neuronal population dynamics in health and disease.

Central and Peripheral Circadian Clocks in Mammals

Abstract: The circadian system of mammals is composed of a hierarchy of oscillators that function at the cellular, tissue, and systems levels. A common molecular mechanism underlies the cell-autonomous circadian oscillator throughout the body, yet this clock system is adapted to different functional contexts. In the central suprachiasmatic nucleus (SCN) of the hypothalamus, a coupled population of neuronal circadian oscillators acts as a master pacemaker for the organism to drive rhythms in activity and rest, feeding, body temperature, and hormones. Coupling within the SCN network confers robustness to the SCN pacemaker, which in turn provides stability to the overall temporal architecture of the organism. Throughout the majority of the cells in the body, cell-autonomous circadian clocks are intimately enmeshed within metabolic pathways. Thus, an emerging view for the adaptive significance of circadian clocks is their fundamental role in orchestrating metabolism.

The complement system: an unexpected role in synaptic pruning during development and disease.

Abstract: An unexpected role for the classical complement cascade in the elimination of central nervous system (CNS) synapses has recently been discovered. Complement proteins are localized to developing CNS synapses during periods of active synapse elimination and are required for normal brain wiring. The function of complement proteins in the brain appears analogous to their function in the immune system: clearance of cellular material that has been tagged for elimination. Similarly, synapses tagged with complement proteins may be eliminated by microglial cells expressing complement receptors. In addition, developing astrocytes release signals that induce the expression of complement components in the CNS. In the mature brain, early synapse loss is a hallmark of several neurodegenerative diseases. Complement proteins are profoundly upregulated in many CNS diseases prior to signs of neuron loss, suggesting a reactivation of similar developmental mechanisms of complementmediated synapse elimination potentially driving disease progression.

The Neural Basis of Empathy

Abstract: Empathy—the ability to share the feelings of others—is fundamental to our emotional and social lives. Previous human imaging studies focusing on empathy for others' pain have consistently shown activations in regions also involved in the direct pain experience, particularly anterior insula and anterior and midcingulate cortex. These findings suggest that empathy is, in part, based on shared representations for firsthand and vicarious experiences of affective states. Empathic responses are not static but can be modulated by person characteristics, such as degree of alexithymia. It has also been shown that contextual appraisal, including perceived fairness or group membership of others, may modulate empathic neuronal activations. Empathy often involves coactivations in further networks associated with social cognition, depending on the specific situation and information available in the environment. Empathy-related insular and cingulate activity may reflect domain-general computations representing and predi...

The restless engram: consolidations never end.

Abstract: Memory consolidation is the hypothetical process in which an item in memory is transformed into a long-term form. It is commonly addressed at two complementary levels of description and analysis: the cellular/synaptic level (synaptic consolidation) and the brain systems level (systems consolidation). This article focuses on selected recent advances in consolidation research, including the reconsolidation of long-term memory items, the brain mechanisms of transformation of the content and of cue-dependency of memory items over time, as well as the role of rest and sleep in consolidating and shaping memories. Taken together, the picture that emerges is of dynamic engrams that are formed, modified, and remodified over time at the systems level by using synaptic consolidation mechanisms as subroutines. This implies that, contrary to interpretations that have dominated neuroscience for a while, but similar to long-standing cognitive concepts, consolidation of at least some items in long-term memory may never really come to an end.

Multiple Functions of Endocannabinoid Signaling in the Brain

Abstract: Despite being regarded as a hippie science for decades, cannabinoid research has finally found its well-deserved position in mainstream neuroscience. A series of groundbreaking discoveries revealed that endocannabinoid molecules are as widespread and important as conventional neurotransmitters such as glutamate or GABA, yet they act in profoundly unconventional ways. We aim to illustrate how uncovering the molecular, anatomical, and physiological characteristics of endocannabinoid signaling has revealed new mechanistic insights into several fundamental phenomena in synaptic physiology. First, we summarize unexpected advances in the molecular complexity of biogenesis and inactivation of the two endocannabinoids, anandamide and 2-arachidonoylglycerol. Then, we show how these new metabolic routes are integrated into well-known intracellular signaling pathways. These endocannabinoid-producing signalosomes operate in phasic and tonic modes, thereby differentially governing homeostatic, short-term, and long-ter...

Brain Plasticity Through the Life Span: Learning to Learn and Action Video Games

Abstract: The ability of the human brain to learn is exceptional. Yet, learning is typically quite specific to the exact task used during training, a limiting factor for practical applications such as rehabilitation, workforce training, or education. The possibility of identifying training regimens that have a broad enough impact to transfer to a variety of tasks is thus highly appealing. This work reviews how complex training environments such as action video game play may actually foster brain plasticity and learning. This enhanced learning capacity, termed learning to learn, is considered in light of its computational requirements and putative neural mechanisms.

Neural Basis of Reinforcement Learning and Decision Making

Abstract: Reinforcement learning is an adaptive process in which an animal utilizes its previous experience to improve the outcomes of future choices. Computational theories of reinforcement learning play a central role in the newly emerging areas of neuroeconomics and decision neuroscience. In this framework, actions are chosen according to their value functions, which describe how much future reward is expected from each action. Value functions can be adjusted not only through reward and penalty, but also by the animal's knowledge of its current environment. Studies have revealed that a large proportion of the brain is involved in representing and updating value functions and using them to choose an action. However, how the nature of a behavioral task affects the neural mechanisms of reinforcement learning remains incompletely understood. Future studies should uncover the principles by which different computational elements of reinforcement learning are dynamically coordinated across the entire brain.

Critical-Period Plasticity in the Visual Cortex

Abstract: In many regions of the developing brain, neuronal circuits undergo defined phases of enhanced plasticity, termed critical periods. Work in the rodent visual cortex has led to important insights into the cellular and molecular mechanisms regulating the timing of the critical period. Although there is little doubt that the maturation of specific inhibitory circuits plays a key role in the opening of the critical period in the visual cortex, it is less clear what puts an end to it. In this review, we describe the established mechanisms and point out where more experimental work is needed. We also show that plasticity in the visual cortex is present well before, and long after, the peak of the critical period.

The pathophysiology of fragile X (and what it teaches us about synapses).

Abstract: Fragile X is the most common known inherited cause of intellectual disability and autism, and it typically results from transcriptional silencing of FMR1 and loss of the encoded protein, FMRP (fragile X mental retardation protein). FMRP is an mRNA-binding protein that functions at many synapses to inhibit local translation stimulated by metabotropic glutamate receptors (mGluRs) 1 and 5. Recent studies on the biology of FMRP and the signaling pathways downstream of mGluR1/5 have yielded deeper insight into how synaptic protein synthesis and plasticity are regulated by experience. This new knowledge has also suggested ways that altered signaling and synaptic function can be corrected in fragile X, and human clinical trials based on this information are under way.

Compressed Sensing, Sparsity, and Dimensionality in Neuronal Information Processing and Data Analysis

Abstract: The curse of dimensionality poses severe challenges to both technical and conceptual progress in neuroscience. In particular, it plagues our ability to acquire, process, and model high-dimensional data sets. Moreover, neural systems must cope with the challenge of processing data in high dimensions to learn and operate successfully within a complex world. We review recent mathematical advances that provide ways to combat dimensionality in specific situations. These advances shed light on two dual questions in neuroscience. First, how can we as neuroscientists rapidly acquire high-dimensional data from the brain and subsequently extract meaningful models from limited amounts of these data? And second, how do brains themselves process information in their intrinsically high-dimensional patterns of neural activity as well as learn meaningful, generalizable models of the external world from limited experience?

Under Pressure: Cellular and Molecular Responses During Glaucoma, a Common Neurodegeneration with Axonopathy

Abstract: Glaucoma is a complex neurodegenerative disorder that is expected to affect 80 million people by the end of this decade. Retinal ganglion cells (RGCs) are the most affected cell type and progressively degenerate over the course of the disease. RGC axons exit the eye and enter the optic nerve by passing through the optic nerve head (ONH). The ONH is an important site of initial damage in glaucoma. Higher intraocular pressure (IOP) is an important risk factor for glaucoma, but the molecular links between elevated IOP and axon damage in the ONH are poorly defined. In this review and focusing primarily on the ONH, we discuss recent studies that have contributed to understanding the etiology and pathogenesis of glaucoma. We also identify areas that require further investigation and focus on mechanisms identified in other neurodegenerations that may contribute to RGC dysfunction and demise in glaucoma.

Cellular Pathways of Hereditary Spastic Paraplegia

Abstract: Human voluntary movement is controlled by the pyramidal motor system, a long CNS pathway comprising corticospinal and lower motor neurons. Hereditary spastic paraplegias (HSPs) are a large, genetically diverse group of inherited neurologic disorders characterized by a length-dependent distal axonopathy of the corticospinal tracts, resulting in lower limb spasticity and weakness. A range of studies are converging on alterations in the shaping of organelles, particularly the endoplasmic reticulum, as well as intracellular membrane trafficking and distribution as primary defects underlying the HSPs, with clear relevance for other long axonopathies affecting peripheral nerves and lower motor neurons.

Decision-Related Activity in Sensory Neurons: Correlations Among Neurons and with Behavior

Abstract: Neurons in early sensory cortex show weak but systematic correlations with perceptual decisions when trained animals perform at psychophysical threshold. These correlations are observed across repeated presentations of identical stimuli and cannot be explained by variation in external factors. The relationship between the activity of individual sensory neurons and the animal's behavioral choice means that even neurons in early sensory cortex carry information about an upcoming decision. This relationship, termed choice probability, may reflect the effect of fluctuations in neuronal firing rate on the animal's decision, but it can also reflect modulation of sensory responses by cognitive factors, or network properties such as variability that is shared among populations of neurons. Here, we review recent work clarifying the relationship among fluctuations in the responses of individual neurons, correlated variability, and behavior in a variety of tasks and cortical areas. We also discuss the possibility th...

Circuits for Skilled Reaching and Grasping

Abstract: From an evolutionary perspective, it is clear that basic motor functions such as locomotion and posture are largely controlled by neural circuitries residing in the spinal cord and brain-stem. The control of voluntary movements such as skillful reaching and grasping is generally considered to be governed by neural circuitries in the motor cortex that connect directly to motoneurons via the corticomotoneuronal (CM) pathway. The CM pathway may act together with several brain-stem systems that also act directly with motoneurons. This simple view was challenged by work in the cat, which lacks the direct CM system, showing that the motor commands for reaching and grasping could be mediated via spinal interneurons with input from the motor-cortex and brain-stem systems. It was further demonstrated that the spinal interneurons mediating the descending commands for reaching and grasping constitute separate and distinct populations from those involved in locomotion and posture. The aim of this review is to describe populations of spinal interneurons that are involved in the control of skilled reaching and grasping in the cat, monkey, and human.

The Physiology of the Axon Initial Segment

Abstract: The action potential generally begins in the axon initial segment (AIS), a principle confirmed by 60 years of research; however, the most recent advances have shown that a very rich biology underlies this simple observation. The AIS has a remarkably complex molecular composition, with a wide variety of ion channels and attendant mechanisms for channel localization, and may feature membrane domains each with distinct roles in excitation. Its function may be regulated in the short term through the action of neurotransmitters, in the long term through activity- and Ca(2+)-dependent processes. Thus, the AIS is not merely the beginning of the axon, but rather a key site in the control of neuronal excitability.

Attractor Dynamics of Spatially Correlated Neural Activity in the Limbic System

Abstract: Attractor networks are a popular computational construct used to model different brain systems. These networks allow elegant computations that are thought to represent a number of aspects of brain function. Although there is good reason to believe that the brain displays attractor dynamics, it has proven difficult to test experimentally whether any particular attractor architecture resides in any particular brain circuit. We review models and experimental evidence for three systems in the rat brain that are presumed to be components of the rat's navigational and memory system. Head-direction cells have been modeled as a ring attractor, grid cells as a plane attractor, and place cells both as a plane attractor and as a point attractor. Whereas the models have proven to be extremely useful conceptual tools, the experimental evidence in their favor, although intriguing, is still mostly circumstantial.

The Auditory Hair Cell Ribbon Synapse: From Assembly to Function

Abstract: Cochlear inner hair cells (IHCs), the mammalian auditory sensory cells, encode acoustic signals with high fidelity by Graded variations of their membrane potential trigger rapid and sustained vesicle exocytosis at their ribbon synapses. The kinetics of glutamate release allows proper transfer of sound information to the primary afferent auditory neurons. Understanding the physiological properties and underlying molecular mechanisms of the IHC synaptic machinery, and especially its high temporal acuity, which is pivotal to speech perception, is a central issue of auditory science. During the past decade, substantial progress in high-resolution imaging and electrophysiological recordings, as well as the development of genetic approaches both in humans and in mice, has produced major insights regarding the morphological, physiological, and molecular characteristics of this synapse. Here we review this recent knowledge and discuss how it enlightens the way the IHC ribbon synapse develops and functions.

The Role of Organizers in Patterning the Nervous System

Abstract: The foundation for the anatomical and functional complexity of the vertebrate central nervous system is laid during embryogenesis. After Spemann's organizer and its derivatives have endowed the neural plate with a coarse pattern along its anteroposterior and mediolateral axes, this basis is progressively refined by the activity of secondary organizers within the neuroepithelium that function by releasing diffusible signaling factors. Dorsoventral patterning is mediated by two organizer regions that extend along the dorsal and ventral midlines of the entire neuraxis, whereas anteroposterior patterning is controlled by several discrete organizers. Here we review how these secondary organizers are established and how they exert their signaling functions. Organizer signals come from a surprisingly limited set of signaling factor families, indicating that the competence of target cells to respond to those signals plays an important part in neural patterning.

Primary visual cortex: awareness and blindsight.

Abstract: The primary visual cortex (V1) is the principal telencephalic recipient of visual input in humans and monkeys. It is unique among cortical areas in that its destruction results in chronic blindness. However, certain patients with V1 damage, though lacking visual awareness, exhibit visually guided behavior: blindsight. This phenomenon, together with evidence from electrophysiological, neuroimaging, and psychophysical experiments, has led to speculation that V1 activity has a special or direct role in generating conscious perception. To explore this issue, this article reviews experiments that have used two powerful paradigms--stimulus-induced perceptual suppression and chronic V1 ablation--each of which disrupts the ability to perceive salient visual stimuli. Focus is placed on recent neurophysiological, behavioral, and functional imaging studies from the nonhuman primate that shed light on V1's role in conscious awareness. In addition, anatomical pathways that relay visual information to the cortex during normal vision and in blindsight are reviewed. Although the critical role of V1 in primate vision follows naturally from its position as a bottleneck of visual signals, little evidence supports its direct contribution to visual awareness.

Evolution of Synapse Complexity and Diversity

Abstract: Proteomic studies of the composition of mammalian synapses have revealed a high degree of complexity. The postsynaptic and presynaptic terminals are molecular systems with highly organized protein networks producing emergent physiological and behavioral properties. The major classes of synapse proteins and their respective functions in intercellular communication and adaptive responses evolved in prokaryotes and eukaryotes prior to the origins of neurons in metazoa. In eukaryotes, the organization of individual proteins into multiprotein complexes comprising scaffold proteins, receptors, and signaling enzymes formed the precursor to the core adaptive machinery of the metazoan postsynaptic terminal. Multiplicative increases in the complexity of this protosynapse machinery secondary to genome duplications drove synaptic, neuronal, and behavioral novelty in vertebrates. Natural selection has constrained diversification in mammalian postsynaptic mechanisms and the repertoire of adaptive and innate behaviors. The evolution and organization of synapse proteomes underlie the origins and complexity of nervous systems and behavior.

Functional Consequences of Mutations in Postsynaptic Scaffolding Proteins and Relevance to Psychiatric Disorders

Abstract: Functional studies on postsynaptic scaffolding proteins at excitatory synapses have revealed a plethora of important roles for synaptic structure and function. In addition, a convergence of recent in vivo functional evidence together with human genetics data strongly suggest that mutations in a variety of these postsynaptic scaffolding proteins may contribute to the etiology of diverse human psychiatric disorders such as schizophrenia, autism spectrum disorders, and obsessive-compulsive spectrum disorders. Here we review the most recent evidence for several key postsynaptic scaffolding protein families and explore how mouse genetics and human genetics have intersected to advance our knowledge concerning the contributions of these important players to complex brain function and dysfunction.

Early Events in Axon/Dendrite Polarization

Abstract: Differentiation of axons and dendrites is a critical step in neuronal development. Here we review the evidence that axon/dendrite formation during neuronal polarization depends on the intrinsic cytoplasmic asymmetry inherited by the postmitotic neuron, the exposure of the neuron to extracellular chemical factors, and the action of anisotropic mechanical forces imposed by the environment. To better delineate the functions of early signals among a myriad of cellular components that were shown to influence axon/dendrite formation, we discuss their functions by distinguishing their roles as determinants, mediators, or modulators and consider selective degradation of these components as a potential mechanism for axon/dendrite polarization. Finally, we examine whether these early events of axon/dendrite formation involve local autocatalytic activation and long-range inhibition, as postulated by Alan Turing for the morphogenesis of patterned biological structure.

Social Control of the Brain

Abstract: In the course of evolution, social behavior has been a strikingly potent selective force in shaping brains to control action. Physiological, cellular, and molecular processes reflect this evolutionary force, particularly in the regulation of reproductive behavior and its neural circuitry. Typically, experimental analysis is directed at how the brain controls behavior, but the brain is also changed by behavior over evolution, during development, and through its ongoing function. Understanding how the brain is influenced by behavior offers unusual experimental challenges. General principles governing the social regulation of the brain are most evident in the control of reproductive behavior. This is most likely because reproduction is arguably the most important event in an animal's life and has been a powerful and essential selective force over evolution. Here I describe the mechanisms through which behavior changes the brain in the service of reproduction using a teleost fish model system.

What Is the Brain-Cancer Connection?

Abstract: A focus of much cancer research is at the molecular and cellular levels. In contrast, the effects of social interactions and psychological state are less investigated, and considered by many a “soft” science. Yet several highly rigorous studies have begun to tease out biochemical pathways by which the brain can influence the development and growth of cancer. Previous reviews have discussed the concept of stress and cancer. Here, we discuss recent work showing environments that are more complex and challenging, but not stressful per se, and that have robust effects on peripheral cancer by activating a specific neuroendocrine brain-adipocyte axis. These enriched environments lead to activation of the sympathetic innervation of fat tissue, suppression of leptin, and a reduction in cancer proliferation by inducing hypothalamic BDNF expression. We summarize this work and discuss how these data integrate into the body of literature regarding stress, the environment, and cancer.