Annual Review of Neuroscience - Volume 32, 2009

Neuropathic pain is triggered by lesions to the somatosensory nervous system that alter its structure and function so that pain occurs spontaneously and responses to noxious and innocuous stimuli are pathologically amplified. The pain is an expression of maladaptive plasticity within the nociceptive system, a series of changes that constitute a neural disease state. Multiple alterations distributed widely across the nervous system contribute to complex pain phenotypes. These alterations include ectopic generation of action potentials, facilitation and disinhibition of synaptic transmission, loss of synaptic connectivity and formation of new synaptic circuits, and neuroimmune interactions. Although neural lesions are necessary, they are not sufficient to generate neuropathic pain; genetic polymorphisms, gender, and age all influence the risk of developing persistent pain. Treatment needs to move from merely suppressing symptoms to a disease-modifying strategy aimed at both preventing maladaptive plasticity and reducing intrinsic risk.

Sensory experience and learning alter sensory representations in cerebral cortex. The synaptic mechanisms underlying sensory cortical plasticity have long been sought. Recent work indicates that long-term cortical plasticity is a complex, multicomponent process involving multiple synaptic and cellular mechanisms. Sensory use, disuse, and training drive long-term potentiation and depression (LTP and LTD), homeostatic synaptic plasticity and plasticity of intrinsic excitability, and structural changes including formation, removal, and morphological remodeling of cortical synapses and dendritic spines. Both excitatory and inhibitory circuits are strongly regulated by experience. This review summarizes these findings and proposes that these mechanisms map onto specific functional components of plasticity, which occur in common across the primary somatosensory, visual, and auditory cortices.

Mood disorders collectively account for a substantial proportion of disease burden across the globe and have a devastating impact on quality of life and occupational function. Here we evaluate recent progress in understanding the neurocognitive mechanisms involved in the manifestation of mood disorders. We focus on four domains of cognitive function that are altered in patients with depression: executive control, memory, affective processing, and feedback sensitivity. These alterations implicate a distributed neural circuit composed of multiple sectors of the prefrontal cortex in interaction with subcortical regions (striatum, thalamus) and temporal lobe structures (amygdala, hippocampus). Affective processing and feedback sensitivity are highly sensitive to serotonergic manipulation and are targeted by antidepressant treatments. By drawing together cognitive, neuroanatomical, and pharmacological tiers of research, we identify treatment targets and directions for future investigation to identify people at risk, minimize relapse, and maximize long-term beneficial outcomes for those suffering from depression.

Diffusion imaging can be used to estimate the routes taken by fiber pathways connecting different regions of the living brain. This approach has already supplied novel insights into in vivo human brain anatomy. For example, by detecting where connection patterns change, one can define anatomical borders between cortical regions or subcortical nuclei in the living human brain for the first time. Because diffusion tractography is a relatively new technique, however, it is important to assess its validity critically. We discuss the degree to which diffusion tractography meets the requirements of a technique to assess structural connectivity and how its results compare to those from the gold-standard tract tracing methods in nonhuman animals. We conclude that although tractography offers novel opportunities it also raises significant challenges to be addressed by further validation studies to define precisely the limitations and scope of this exciting new technique.

Serotonin is a neuromodulator that is extensively entangled in fundamental aspects of brain function and behavior. We present a computational view of its involvement in the control of appetitively and aversively motivated actions. We first describe a range of its effects in invertebrates, endowing specific structurally fixed networks with plasticity at multiple spatial and temporal scales. We then consider its rather widespread distribution in the mammalian brain. We argue that this is associated with a more unified representational and functional role in aversive processing that is amenable to computational analyses with the kinds of reinforcement learning techniques that have helped elucidate dopamine's role in appetitive behavior. Finally, we suggest that it is only a partial reflection of dopamine because of essential asymmetries between the natural statistics of rewards and punishments.

The basal ganglia occupy the core of the forebrain and consist of evolutionarily conserved motor nuclei that form recurrent circuits critical for motivation and motor planning. The striatum is the main input nucleus of the basal ganglia and a key neural substrate for procedural learning and memory. The vast majority of striatal neurons are spiny GABAergic projection neurons, which exhibit slow but temporally precise spiking in vivo. Contributing to this precision are several different types of interneurons that constitute only a small fraction of total neuron number but play a critical role in regulating striatal output. This review examines the cellular physiology and modulation of striatal neurons that give rise to their unique properties and function.

Glial cells were long considered end products of neural differentiation, specialized supportive cells with an origin very different from that of neurons. New studies have shown that some glial cells—radial glia (RG) in development and specific subpopulations of astrocytes in adult mammals—function as primary progenitors or neural stem cells (NSCs). This is a fundamental departure from classical views separating neuronal and glial lineages early in development. Direct visualization of the behavior of NSCs and lineage-tracing studies reveal how neuronal lineages emerge. In development and in the adult brain, many neurons and glial cells are not the direct progeny of NSCs, but instead originate from transit amplifying, or intermediate, progenitor cells (IPCs). Within NSCs and IPCs, genetic programs unfold for generating the extraordinary diversity of cell types in the central nervous system. The timing in development and location of NSCs, a property tightly linked to their neuroepithelial origin, appear to be the key determinants of the types of neurons generated. Identification of NSCs and IPCs is critical to understand brain development and adult neurogenesis and to develop new strategies for brain repair.

Number symbols have allowed humans to develop superior mathematical skills that are a hallmark of technologically advanced cultures. Findings in animal cognition, developmental psychology, and anthropology indicate that these numerical skills are rooted in nonlinguistic biological primitives. Recent studies in human and nonhuman primates using a broad range of methodologies provide evidence that numerical information is represented and processed by regions of the prefrontal and posterior parietal lobes, with the intraparietal sulcus as a key node for the representation of the semantic aspect of numerical quantity.

Neuronal gamma-band synchronization is found in many cortical areas, is induced by different stimuli or tasks, and is related to several cognitive capacities. Thus, it appears as if many different gamma-band synchronization phenomena subserve many different functions. I argue that gamma-band synchronization is a fundamental process that subserves an elemental operation of cortical computation. Cortical computation unfolds in the interplay between neuronal dynamics and structural neuronal connectivity. A core motif of neuronal connectivity is convergence, which brings about both selectivity and invariance of neuronal responses. However, those core functions can be achieved simultaneously only if converging neuronal inputs are functionally segmented and if only one segment is selected at a time. This segmentation and selection can be elegantly achieved if structural connectivity interacts with neuronal synchronization. I propose that this process is at least one of the fundamental functions of gamma-band synchronization, which then subserves numerous higher cognitive functions.

Neuroimaging, especially BOLD fMRI, has begun to identify how variability in brain function contributes to individual differences in complex behavioral traits. In parallel, pharmacological fMRI and multimodal PET/fMRI are identifying how variability in molecular signaling pathways influences individual differences in brain function. Against this background, functional genetic polymorphisms are being utilized to understand the origins of variability in signaling pathways as well as to model efficiently how such emergent variability impacts behaviorally relevant brain function. This article provides an overview of a research strategy seeking to integrate these complementary technologies and utilizes existing empirical data to illustrate its effectiveness in illuminating the neurobiology of individual differences in complex behavioral traits. The article also discusses how such efforts can contribute to the identification of predictive markers that interact with environmental factors to precipitate disease and to develop more effective and individually tailored treatment regimes.

The ultimate goal of neural interface research is to create links between the nervous system and the outside world either by stimulating or by recording from neural tissue to treat or assist people with sensory, motor, or other disabilities of neural function. Although electrical stimulation systems have already reached widespread clinical application, neural interfaces that record neural signals to decipher movement intentions are only now beginning to develop into clinically viable systems to help paralyzed people. We begin by reviewing state-of-the-art research and early-stage clinical recording systems and focus on systems that record single-unit action potentials. We then address the potential for neural interface research to enhance basic scientific understanding of brain function by offering unique insights in neural coding and representation, plasticity, brain-behavior relations, and the neurobiology of disease. Finally, we discuss technical and scientific challenges faced by these systems before they are widely adopted by severely motor-disabled patients.

We review the modulatory effects of the catecholamine neurotransmitters noradrenaline and dopamine on prefrontal cortical function. The effects of pharmacologic manipulations of these systems, sometimes in comparison with the indoleamine serotonin (5-HT), on performance on a variety of tasks that tap working memory, attentional-set formation and shifting, reversal learning, and response inhibition are compared in rodents, nonhuman primates, and humans using, in a behavioral context, several techniques ranging from microiontophoresis and single-cell electrophysiological recording to pharmacologic functional magnetic resonance imaging. Dissociable effects of drugs and neurotoxins affecting these monoamine systems suggest new ways of conceptualizing state-dependent fronto-executive functions, with implications for understanding the molecular genetic basis of mental illness and its treatment.

Fear arousal, initiated by an environmental threat, leads to activation of the stress response, a state of alarm that promotes an array of autonomic and endocrine changes designed to aid self-preservation. The stress response includes the release of glucocorticoids from the adrenal cortex and catecholamines from the adrenal medulla and sympathetic nerves. These stress hormones, in turn, provide feedback to the brain and influence neural structures that control emotion and cognition. To illustrate this influence, we focus on how it impacts fear conditioning, a behavioral paradigm widely used to study the neural mechanisms underlying the acquisition, expression, consolidation, reconsolidation, and extinction of emotional memories. We also discuss how stress and the endocrine mediators of the stress response influence the morphological and electrophysiological properties of neurons in brain areas that are crucial for fear-conditioning processes, including the amygdala, hippocampus, and prefrontal cortex. The information in this review illuminates the behavioral and cellular events that underlie the feedforward and feedback networks that mediate states of fear and stress and their interaction in the brain.

Over the past decade, renewed interest in the auditory system has resulted in a surge of anatomical and physiological research in the primate auditory cortex and its targets. Anatomical studies have delineated multiple areas in and around primary auditory cortex and demonstrated connectivity among these areas, as well as between these areas and the rest of the cortex, including prefrontal cortex. Physiological recordings of auditory neurons have found that species-specific vocalizations are useful in probing the selectivity and potential functions of acoustic neurons. A number of cortical regions contain neurons that are robustly responsive to vocalizations, and some auditory responsive neurons show more selectivity for vocalizations than for other complex sounds. Demonstration of selectivity for vocalizations has prompted the question of which features are encoded by higher-order auditory neurons. Results based on detailed studies of the structure of these vocalizations, as well as the tuning and information-coding properties of neurons sensitive to these vocalizations, have begun to provide answers to this question. In future studies, these and other methods may help to define the way in which cells, ensembles, and brain regions process communication sounds. Moreover, the discovery that several nonprimary auditory cortical regions may be multisensory and responsive to vocalizations with corresponding facial gestures may change the way in which we view the processing of communication information by the auditory system.

Neurons are among the most highly polarized cell types in the body, and the polarization of axon and dendrites underlies the ability of neurons to integrate and transmit information in the brain. Significant progress has been made in the identification of the cellular and molecular mechanisms underlying the establishment of neuronal polarity using primarily in vitro approaches such as dissociated culture of rodent hippocampal and cortical neurons. This model has led to the predominant view suggesting that neuronal polarization is specified largely by stochastic, asymmetric activation of intracellular signaling pathways. Recent evidence shows that extracellular cues can play an instructive role during neuronal polarization in vitro and in vivo. In this review, we synthesize the recent data supporting an integrative model whereby extracellular cues orchestrate the intracellular signaling underlying the initial break of neuronal symmetry leading to axon-dendrite polarization.

The development of precise connectivity patterns during the establishment of the nervous system depends on the regulated action of diverse, conserved families of guidance cues and their neuronal receptors. Determining how these signaling pathways function to regulate axon growth and guidance is fundamentally important to understanding wiring specificity in the nervous system and will undoubtedly shed light on many neural developmental disorders. Considerable progress has been made in defining the mechanisms that regulate the correct spatial and temporal distribution of guidance receptors and how these receptors in turn signal to the growth cone cytoskeleton to control steering decisions. This review focuses on recent advances in our understanding of the mechanisms mediating growth cone guidance with a particular emphasis on the control of guidance receptor regulation and signaling.

Does the cerebellum influence nonmotor behavior? Recent anatomical studies demonstrate that the output of the cerebellum targets multiple nonmotor areas in the prefrontal and posterior parietal cortex, as well as the cortical motor areas. The projections to different cortical areas originate from distinct output channels within the cerebellar nuclei. The cerebral cortical area that is the main target of each output channel is a major source of input to the channel. Thus, a closed-loop circuit represents the major architectural unit of cerebro-cerebellar interactions. The outputs of these loops provide the cerebellum with the anatomical substrate to influence the control of movement and cognition. Neuroimaging and neuropsychological data supply compelling support for this view. The range of tasks associated with cerebellar activation is remarkable and includes tasks designed to assess attention, executive control, language, working memory, learning, pain, emotion, and addiction. These data, along with the revelations about cerebro-cerebellar circuitry, provide a new framework for exploring the contribution of the cerebellum to diverse aspects of behavior.

Since the work of Golgi and Cajal, light microscopy has remained a key tool for neuroscientists to observe cellular properties. Ongoing advances have enabled new experimental capabilities using light to inspect the nervous system across multiple spatial scales, including ultrastructural scales finer than the optical diffraction limit. Other progress permits functional imaging at faster speeds, at greater depths in brain tissue, and over larger tissue volumes than previously possible. Portable, miniaturized fluorescence microscopes now allow brain imaging in freely behaving mice. Complementary progress on animal preparations has enabled imaging in head-restrained behaving animals, as well as time-lapse microscopy studies in the brains of live subjects. Mouse genetic approaches permit mosaic and inducible fluorescence-labeling strategies, whereas intrinsic contrast mechanisms allow in vivo imaging of animals and humans without use of exogenous markers. This review surveys such advances and highlights emerging capabilities of particular interest to neuroscientists.