Annual Review of Neuroscience - Volume 37, 2014

According to embodied cognition theories, higher cognitive abilities depend on the reenactment of sensory and motor representations. In the first part of this review, we critically analyze the central claims of embodied theories and argue that the existing behavioral and neuroimaging data do not allow investigators to discriminate between embodied cognition and classical cognitive accounts, which assume that conceptual representations are amodal and symbolic. In the second part, we review the main claims and the core electrophysiological findings typically cited in support of the mirror neuron theory of action understanding, one of the most influential examples of embodied cognition theories. In the final part, we analyze the claim that mirror neurons subserve action understanding by mapping visual representations of observed actions on motor representations, trying to clarify in what sense the representations carried by these neurons can be claimed motor.

Activity-dependent changes in the strength of synaptic connections are fundamental to the formation and maintenance of memory. The mechanisms underlying persistent changes in synaptic strength in the hippocampus, specifically long-term potentiation and depression, depend on new protein synthesis. Such changes are thought to be orchestrated by engaging the signaling pathways that regulate mRNA translation in neurons. In this review, we discuss the key regulatory pathways that govern translational control in response to synaptic activity and the mRNA populations that are specifically targeted by these pathways. The critical contribution of regulatory control over new protein synthesis to proper cognitive function is underscored by human disorders associated with either silencing or mutation of genes encoding proteins that directly regulate translation. In light of these clinical implications, we also consider the therapeutic potential of targeting dysregulated translational control to treat cognitive disorders of synaptic dysfunction.

Anatomically, the perirhinal cortex sits at the boundary between the medial temporal lobe and the ventral visual pathway. It has prominent interconnections not only with both these systems, but also with a wide range of unimodal and polymodal association areas. Consistent with these diverse projections, neurophysiological studies reveal a multidimensional set of mnemonic signals that include stimulus familiarity, within- and between-domain associations, associative recall, and delay-based persistence. This wide range of perirhinal memory signals not only includes signals that are largely unique to the perirhinal cortex (i.e., object familiarity), consistent with dual-process theories, but also includes a range of signals (i.e., associative flexibility and recall) that are strongly associated with the hippocampus, consistent with single-process theories. These neurophysiological findings have important implications for bridging the gap between single-process and dual-process models of medial temporal lobe function.

Autophagy is a conserved catabolic process that delivers the cytosol and cytosolic constituents to the lysosome. Its fundamental role is to maintain cellular homeostasis and to protect cells from varying insults, including misfolded proteins and damaged organelles. Beyond these roles, the highly specialized cells of the brain have further adapted autophagic pathways to suit their distinct needs. In this review, we briefly summarize our current understanding of the different forms of autophagy and then offer a closer look at how these pathways impact neuronal and glial functions. The emerging evidence indicates that not only are autophagy pathways essential for neural health, but they have a direct impact on developmental and neurodegenerative processes. Taken together, as we unravel the complex roles autophagy pathways play, we will gain the necessary insight to modify these pathways to protect the human brain and treat neurodegenerative diseases.

The vast majority of Alzheimer's disease (AD) cases are late onset (LOAD), which is genetically complex with heritability estimates up to 80%. Apolipoprotein E (APOE) has been irrefutably recognized as the major genetic risk factor, with semidominant inheritance, for LOAD. Although the mechanisms that underlie the pathogenic nature of APOE in AD are still not completely understood, emerging data suggest that APOE contributes to AD pathogenesis through both amyloid-β (Aβ)-dependent and Aβ-independent pathways. Given the central role for APOE in the modulation of AD pathogenesis, many therapeutic strategies have emerged, including converting APOE conformation, regulating APOE expression, mimicking APOE peptides, blocking the APOE/Aβ interaction, modulating APOE lipidation state, and gene therapy. Accumulating evidence also suggests the utility of APOE genotyping in AD diagnosis, risk assessment, prevention, and treatment response.

The basic elements of animal behavior that are critical to survival include energy, arousal, and motivation: Energy intake and expenditure are fundamental to all organisms for the performance of any type of function; according to the Yerkes-Dodson law, an optimal level of arousal is required for animals to perform normal functions; and motivation is critical to goal-oriented behaviors in higher animals. The brain is the primary organ that controls these elements and, through evolution, has developed specialized structures to accomplish this task. The orexin/hypocretin system in the perifornical/lateral hypothalamus, which was discovered 15 years ago, is one such specialized area. This review summarizes a fast-growing body of evidence discerning how the orexin/hypocretin system integrates internal and external cues to regulate energy intake that can then be used to generate sufficient arousal for animals to perform innate and goal-oriented behaviors.

The basal ganglia are a series of interconnected subcortical nuclei. The function and dysfunction of these nuclei have been studied intensively in motor control, but more recently our knowledge of these functions has broadened to include prominent roles in cognition and affective control. This review summarizes historical models of basal ganglia function, as well as findings supporting or conflicting with these models, while emphasizing recent work in animals and humans directly testing the hypotheses generated by these models.

Parkinson's disease (PD) is a common neurodegenerative disease, yet the underlying causative molecular mechanisms are ill defined. Numerous observations based on drug studies and mutations in genes that cause PD point to a complex set of rather subtle mitochondrial defects that may be causative. Indeed, intensive investigation of these genes in model organisms has revealed roles in the electron transport chain, mitochondrial protein homeostasis, mitophagy, and the fusion and fission of mitochondria. Here, we attempt to synthesize results from experimental studies in diverse systems to define the precise function of these PD genes, as well as their interplay with other genes that affect mitochondrial function. We propose that subtle mitochondrial defects in combination with other insults trigger the onset and progression of disease, in both familial and idiopathic PD.

Functional magnetic resonance imaging (fMRI) provides a unique view of the working human mind. The blood-oxygen-level-dependent (BOLD) signal, detected in fMRI, reflects changes in deoxyhemoglobin driven by localized changes in brain blood flow and blood oxygenation, which are coupled to underlying neuronal activity by a process termed neurovascular coupling. Over the past 10 years, a range of cellular mechanisms, including astrocytes, pericytes, and interneurons, have been proposed to play a role in functional neurovascular coupling. However, the field remains conflicted over the relative importance of each process, while key spatiotemporal features of BOLD response remain unexplained. Here, we review current candidate neurovascular coupling mechanisms and propose that previously overlooked involvement of the vascular endothelium may provide a more complete picture of how blood flow is controlled in the brain. We also explore the possibility and consequences of conditions in which neurovascular coupling may be altered, including during postnatal development, pathological states, and aging, noting relevance to both stimulus-evoked and resting-state fMRI studies.

Facial muscles drive whisker movements, which are important for active tactile sensory perception in mice and rats. These whisker muscles are innervated by cholinergic motor neurons located in the lateral facial nucleus. The whisker motor neurons receive synaptic inputs from premotor neurons, which are located within the brain stem, the midbrain, and the neocortex. Complex, distributed neural circuits therefore regulate whisker movement during behavior. This review focuses specifically on cortical whisker motor control. The whisker primary motor cortex (M1) strongly innervates brain stem reticular nuclei containing whisker premotor neurons, which might form a central pattern generator for rhythmic whisker protraction. In a parallel analogous pathway, the whisker primary somatosensory cortex (S1) strongly projects to the brain stem spinal trigeminal interpolaris nucleus, which contains whisker premotor neurons innervating muscles for whisker retraction. These anatomical pathways may play important functional roles, since stimulation of M1 drives exploratory rhythmic whisking, whereas stimulation of S1 drives whisker retraction.

Organisms must act in the face of sensory, motor, and reward uncertainty stemming from a pandemonium of stochasticity and missing information. In many tasks, organisms can make better decisions if they have at their disposal a representation of the uncertainty associated with task-relevant variables. We formalize this problem using Bayesian decision theory and review recent behavioral and neural evidence that the brain may use knowledge of uncertainty, confidence, and probability.

Neural tube defects (NTDs), including spina bifida and anencephaly, are severe birth defects of the central nervous system that originate during embryonic development when the neural tube fails to close completely. Human NTDs are multifactorial, with contributions from both genetic and environmental factors. The genetic basis is not yet well understood, but several nongenetic risk factors have been identified as have possibilities for prevention by maternal folic acid supplementation. Mechanisms underlying neural tube closure and NTDs may be informed by experimental models, which have revealed numerous genes whose abnormal function causes NTDs and have provided details of critical cellular and morphological events whose regulation is essential for closure. Such models also provide an opportunity to investigate potential risk factors and to develop novel preventive therapies.

Adult neurogenesis, a developmental process of generating functionally integrated neurons, occurs throughout life in the hippocampus of the mammalian brain and showcases the highly plastic nature of the mature central nervous system. Significant progress has been made in recent years to decipher how adult neurogenesis contributes to brain functions. Here we review recent findings that inform our understanding of adult hippocampal neurogenesis processes and special properties of adult-born neurons. We further discuss potential roles of adult-born neurons at the circuitry and behavioral levels in cognitive and affective functions and how their dysfunction may contribute to various brain disorders. We end by considering a general model proposing that adult neurogenesis is not a cell-replacement mechanism, but instead maintains a plastic hippocampal neuronal circuit via the continuous addition of immature, new neurons with unique properties and structural plasticity of mature neurons induced by new-neuron integration.

Although the prevalent view of emotion and decision making is derived from the notion that there are dual systems of emotion and reason, a modulatory relationship more accurately reflects the current research in affective neuroscience and neuroeconomics. Studies show two potential mechanisms for affect's modulation of the computation of subjective value and decisions. Incidental affective states may carry over to the assessment of subjective value and the decision, and emotional reactions to the choice may be incorporated into the value calculation. In addition, this modulatory relationship is reciprocal: Changing emotion can change choices. This research suggests that the neural mechanisms mediating the relation between affect and choice vary depending on which affective component is engaged and which decision variables are assessed. We suggest that a detailed and nuanced understanding of emotion and decision making requires characterizing the multiple modulatory neural circuits underlying the different means by which emotion and affect can influence choices.

The basal ganglia are equipped with inhibitory and disinhibitory mechanisms that enable a subject to choose valuable objects and actions. Notably, a value can be determined flexibly by recent experience or stably by prolonged experience. Recent studies have revealed that the head and tail of the caudate nucleus selectively and differentially process flexible and stable values of visual objects. These signals are sent to the superior colliculus through different parts of the substantia nigra so that the animal looks preferentially at high-valued objects, but in different manners. Thus, relying on short-term value memories, the caudate head circuit allows the subject's gaze to move expectantly to recently valued objects. Relying on long-term value memories, the caudate tail circuit allows the subject's gaze to move automatically to previously valued objects. The basal ganglia also contain an equivalent parallel mechanism for action values. Such flexible–stable parallel mechanisms for object and action values create a highly adaptable system for decision making.

Visual motion cues provide animals with critical information about their environment and guide a diverse array of behaviors. The neural circuits that carry out motion estimation provide a well-constrained model system for studying the logic of neural computation. Through a confluence of behavioral, physiological, and anatomical experiments, taking advantage of the powerful genetic tools available in the fruit fly Drosophila melanogaster, an outline of the neural pathways that compute visual motion has emerged. Here we describe these pathways, the evidence supporting them, and the challenges that remain in understanding the circuits and computations that link sensory inputs to behavior. Studies in flies and vertebrates have revealed a number of functional similarities between motion-processing pathways in different animals, despite profound differences in circuit anatomy and structure. The fact that different circuit mechanisms are used to achieve convergent computational outcomes sheds light on the evolution of the nervous system.

Neuromodulation underlies many behavioral states and has been extensively studied in small circuits. This has allowed the systematic exploration of how neuromodulatory substances and the neurons that release them can influence circuit function. The physiological state of a network and its level of activity can have profound effects on how the modulators act, a phenomenon known as state dependence. We provide insights from experiments and computational work that show how state dependence can arise and the consequences it can have for cellular and circuit function. These observations pose a general unsolved question that is relevant to all nervous systems: How is robust modulation achieved in spite of animal-to-animal variability and degenerate, nonlinear mechanisms for the production of neuronal and network activity?

A hallmark of human language is that we combine lexical building blocks retrieved from memory in endless new ways. This combinatorial aspect of language is referred to as unification. Here we focus on the neurobiological infrastructure for syntactic and semantic unification. Unification is characterized by a high-speed temporal profile including both prediction and integration of retrieved lexical elements. A meta-analysis of numerous neuroimaging studies reveals a clear dorsal/ventral gradient in both left inferior frontal cortex and left posterior temporal cortex, with dorsal foci for syntactic processing and ventral foci for semantic processing. In addition to core areas for unification, further networks need to be recruited to realize language-driven communication to its full extent. One example is the theory of mind network, which allows listeners and readers to infer the intended message (speaker meaning) from the coded meaning of the linguistic utterance. This indicates that sensorimotor simulation cannot handle all of language processing.

How is sensory information represented in the brain? A long-standing debate in neural coding is whether and how timing of spikes conveys information to downstream neurons. Although we know that neurons in the olfactory bulb (OB) exhibit rich temporal dynamics, the functional relevance of temporal coding remains hotly debated. Recent recording experiments in awake behaving animals have elucidated highly organized temporal structures of activity in the OB. In addition, the analysis of neural circuits in the piriform cortex (PC) demonstrated the importance of not only OB afferent inputs but also intrinsic PC neural circuits in shaping odor responses. Furthermore, new experiments involving stimulation of the OB with specific temporal patterns allowed for testing the relevance of temporal codes. Together, these studies suggest that the relative timing of neuronal activity in the OB conveys odor information and that neural circuits in the PC possess various mechanisms to decode temporal patterns of OB input.

Elucidating the roles of neuronal cell types for physiology and behavior is essential for understanding brain functions. Perturbation of neuron electrical activity can be used to probe the causal relationship between neuronal cell types and behavior. New genetically encoded neuron perturbation tools have been developed for remotely controlling neuron function using small molecules that activate engineered receptors that can be targeted to cell types using genetic methods. Here we describe recent progress for approaches using genetically engineered receptors that selectively interact with small molecules. Called “chemogenetics,” receptors with diverse cellular functions have been developed that facilitate the selective pharmacological control over a diverse range of cell-signaling processes, including electrical activity, for molecularly defined cell types. These tools have revealed remarkably specific behavioral physiological influences for molecularly defined cell types that are often intermingled with populations having different or even opposite functions.

Spatial normalization—applying standardized coordinates as anatomical addresses within a reference space—was introduced to human neuroimaging research nearly 30 years ago. Over these three decades, an impressive series of methodological advances have adopted, extended, and popularized this standard. Collectively, this work has generated a methodologically coherent literature of unprecedented rigor, size, and scope. Large-scale online databases have compiled these observations and their associated meta-data, stimulating the development of meta-analytic methods to exploit this expanding corpus. Coordinate-based meta-analytic methods have emerged and evolved in rigor and utility. Early methods computed cross-study consensus, in a manner roughly comparable to traditional (nonimaging) meta-analysis. Recent advances now compute coactivation-based connectivity, connectivity-based functional parcellation, and complex network models powered from data sets representing tens of thousands of subjects. Meta-analyses of human neuroimaging data in large-scale databases now stand at the forefront of computational neurobiology.

A major challenge for systems neuroscience is to break the neural code. Computational algorithms for encoding information into neural activity and extracting information from measured activity afford understanding of how percepts, memories, thought, and knowledge are represented in patterns of brain activity. The past decade and a half has seen significant advances in the development of methods for decoding human neural activity, such as multivariate pattern classification, representational similarity analysis, hyperalignment, and stimulus-model-based encoding and decoding. This article reviews these advances and integrates neural decoding methods into a common framework organized around the concept of high-dimensional representational spaces.

Significant advances have been made in the behavioral assessment and clinical management of disorders of consciousness (DOC). In addition, functional neuroimaging paradigms are now available to help assess consciousness levels in this challenging patient population. The success of these neuroimaging approaches as diagnostic markers is, however, intrinsically linked to understanding the relationships between consciousness and the brain. In this context, a combined theoretical approach to neuroimaging studies is needed. The promise of such theoretically based markers is illustrated by recent findings that used a perturbational approach to assess the levels of consciousness. Further research on the contents of consciousness in DOC is also needed.

Recent advances in cell reprogramming enable investigators to generate pluripotent stem cells from somatic cells. These induced pluripotent cells can subsequently be differentiated into any cell type, making it possible for the first time to obtain functional human neurons in the lab from control subjects and patients with psychiatric disorders. In this review, we survey the progress made in generating various neuronal subtypes in vitro, with special emphasis on the characterization of these neurons and the identification of unique features of human brain development in a dish. We also discuss efforts to uncover neuronal phenotypes from patients with psychiatric disease and prospects for the use of this platform for drug development.

Sleep and wake are fundamental behavioral states whose molecular regulation remains mysterious. Brain states and body functions change dramatically between sleep and wake, are regulated by circadian and homeostatic processes, and depend on the nutritional and emotional condition of the animal. Sleep-wake transitions require the coordination of several brain regions and engage multiple neurochemical systems, including neuropeptides. Neuropeptides serve two main functions in sleep-wake regulation. First, they represent physiological states such as energy level or stress in response to environmental and internal stimuli. Second, neuropeptides excite or inhibit their target neurons to induce, stabilize, or switch between sleep-wake states. Thus, neuropeptides integrate physiological subsystems such as circadian time, previous neuron usage, energy homeostasis, and stress and growth status to generate appropriate sleep-wake behaviors. We review the roles of more than 20 neuropeptides in sleep and wake to lay the foundation for future studies uncovering the mechanisms that underlie the initiation, maintenance, and exit of sleep and wake states.