Annual Review of Neuroscience - Volume 34, 2011

Visually guided collision avoidance is critical for the survival of many animals. The execution of successful collision-avoidance behaviors requires accurate processing of approaching threats by the visual system and signaling of threat characteristics to motor circuits to execute appropriate motor programs in a timely manner. Consequently, visually guided collision avoidance offers an excellent model with which to study the neural mechanisms of sensory-motor integration in the context of a natural behavior. Neurons that selectively respond to approaching threats and brain areas processing them have been characterized across many species. In locusts in particular, the underlying sensory and motor processes have been analyzed in great detail: These animals possess an identified neuron, called the LGMD, that responds selectively to approaching threats and conveys that information through a second identified neuron, the DCMD, to motor centers, generating escape jumps. A combination of behavioral and in vivo electrophysiological experiments has unraveled many of the cellular and network mechanisms underlying this behavior.

The developmental process of myelination and the adult regenerative process of remyelination share the common objective of investing nerve axons with myelin sheaths. A central question in myelin biology is the extent to which the mechanisms of these two processes are conserved, a concept encapsulated in the recapitulation hypothesis of remyelination. This question also has relevance for translating myelin biology into a better understanding of and eventual treatments for human myelin disorders. Here we review the current evidence for the recapitulation hypothesis and discuss recent findings in the development and regeneration of myelin in the context of human neurological disease.

Object perception is one of the most remarkable capacities of the primate brain. Owing to the large and indeterminate dimensionality of object space, the neural basis of object perception has been difficult to study and remains controversial. Recent work has provided a more precise picture of how 2D and 3D object structure is encoded in intermediate and higher-level visual cortices. Yet, other studies suggest that higher-level visual cortex represents categorical identity rather than structure. Furthermore, object responses are surprisingly adaptive to changes in environmental statistics, implying that learning through evolution, development, and also shorter-term experience during adulthood may optimize the object code. Future progress in reconciling these findings will depend on more effective sampling of the object domain and direct comparison of these competing hypotheses.

Convincing evidence indicates that prenatal exposure to the gonadal hormone, testosterone, influences the development of children's sex-typical toy and activity interests. In addition, growing evidence shows that testosterone exposure contributes similarly to the development of other human behaviors that show sex differences, including sexual orientation, core gender identity, and some, though not all, sex-related cognitive and personality characteristics. In addition to these prenatal hormonal influences, early infancy and puberty may provide additional critical periods when hormones influence human neurobehavioral organization. Sex-linked genes could also contribute to human gender development, and most sex-related characteristics are influenced by socialization and other aspects of postnatal experience, as well. Neural mechanisms underlying the influences of gonadal hormones on human behavior are beginning to be identified. Although the neural mechanisms underlying experiential influences remain largely uninvestigated, they could involve the same neural circuitry as that affected by hormones.

Maintaining the proper balance between excitation and inhibition is critical for the normal function of cortical circuits. This balance is thought to be maintained by an array of homeostatic mechanisms that regulate neuronal and circuit excitability, including mechanisms that target excitatory and inhibitory synapses, and mechanisms that target intrinsic neuronal excitability. In this review, I discuss where and when these mechanisms are used in complex microcircuits, what is currently known about the signaling pathways that underlie them, and how these different ways of achieving network stability cooperate and/or compete. An important challenge for the field of homeostatic plasticity is to assemble our understanding of these individual mechanisms into a coherent view of how microcircuit stability is maintained during experience-dependent circuit refinement.

Nicotine is the principal addictive component that drives continued tobacco use despite users' knowledge of the harmful consequences. The initiation of addiction involves the mesocorticolimbic dopamine system, which contributes to the processing of rewarding sensory stimuli during the overall shaping of successful behaviors. Acting mainly through nicotinic receptors containing the α4 and β2 subunits, often in combination with the α6 subunit, nicotine increases the firing rate and the phasic bursts by midbrain dopamine neurons. Neuroadaptations arise during chronic exposure to nicotine, producing an altered brain condition that requires the continued presence of nicotine to be maintained. When nicotine is removed, a withdrawal syndrome develops. The expression of somatic withdrawal symptoms depends mainly on the α5, α2, and β4 (and likely α3) nicotinic subunits involving the epithalamic habenular complex and its targets. Thus, nicotine taps into diverse neural systems and an array of nicotinic acetylcholine receptor (nAChR) subtypes to influence reward, addiction, and withdrawal.

Failure of axon regeneration after central nervous system (CNS) injuries results in permanent functional deficits. Numerous studies in the past suggested that blocking extracellular inhibitory influences alone is insufficient to allow the majority of injured axons to regenerate, pointing to the importance of revisiting the hypothesis that diminished intrinsic regenerative ability critically underlies regeneration failure. Recent studies in different species and using different injury models have started to reveal important cellular and molecular mechanisms within neurons that govern axon regeneration. This review summarizes these observations and discusses possible strategies for stimulating axon regeneration and perhaps functional recovery after CNS injury.

Monoaminergic neurons are critical functional components of all nervous systems across phylogeny. The terminally differentiated state of individual types of monoaminergic neurons is defined by the coordinated expression of a battery of genes that instructs the synthesis and transport of specific monoamines, such as serotonin or dopamine. Dysfunction or deregulation of several of these enzymes and transporter system has been proposed to be the underlying basis of several pathological conditions. We review here the state of knowledge of the nature of the transcriptional regulatory programs that control the expression of what we term monoaminergic gene batteries (enzymes and transporters for specific monoamines) and thereby define the terminally differentiated state of monoaminergic neurons. We review several case studies in vertebrate and invertebrate model systems and propose that the coordinated expression of the genes that define individual monoaminergic cell types may be brought about by transcriptional coregulatory strategies.

Alzheimer's disease (AD), the leading cause of dementia worldwide, is characterized by the accumulation of the β-amyloid peptide (Aβ) within the brain along with hyperphosphorylated and cleaved forms of the microtubule-associated protein tau. Genetic, biochemical, and behavioral research suggest that physiologic generation of the neurotoxic Aβ peptide from sequential amyloid precursor protein (APP) proteolysis is the crucial step in the development of AD. APP is a single-pass transmembrane protein expressed at high levels in the brain and metabolized in a rapid and highly complex fashion by a series of sequential proteases, including the intramembranous γ-secretase complex, which also process other key regulatory molecules. Why Aβ accumulates in the brains of elderly individuals is unclear but could relate to changes in APP metabolism or Aβ elimination. Lessons learned from biochemical and genetic studies of APP processing will be crucial to the development of therapeutic targets to treat AD.

The mammalian superior colliculus (SC) and its nonmammalian homolog, the optic tectum, constitute a major node in processing sensory information, incorporating cognitive factors, and issuing motor commands. The resulting action—to orient toward or away from a stimulus—can be accomplished as an integrated movement across oculomotor, cephalomotor, and skeletomotor effectors. The SC also participates in preserving fixation during intersaccadic intervals. This review highlights the repertoire of movements attributed to SC function and analyzes the significance of results obtained from causality-based experiments (microstimulation and inactivation). The mechanisms potentially used to decode the population activity in the SC into an appropriate movement command are also discussed.

The responses of neural elements in many sensory areas of the brain vary systematically with their physical position, leading to a topographic representation of the outside world. Sensory representation in the olfactory system has been harder to decipher, in part because it is difficult to find appropriate metrics to characterize odor space and to sample this space densely. Recent experiments have shown that the arrangement of glomeruli, the elementary units of processing, is relatively invariant across individuals in a species, yet it is flexible enough to accommodate new sensors that might be added. Evidence supports the existence of coarse spatial domains carved out on a genetic or functional basis, but a systematic organization of odor responses or neural circuits on a local scale is not evident. Experiments and theory that relate the properties of odorant receptors to the detailed wiring diagram of the downstream olfactory circuits and to behaviors they trigger may reveal the design principles that have emerged during evolution.

Work with patient H.M., beginning in the 1950s, established key principles about the organization of memory that inspired decades of experimental work. Since H.M., the study of human memory and its disorders has continued to yield new insights and to improve understanding of the structure and organization of memory. Here we review this work with emphasis on the neuroanatomy of medial temporal lobe and diencephalic structures important for memory, multiple memory systems, visual perception, immediate memory, memory consolidation, the locus of long-term memory storage, the concepts of recollection and familiarity, and the question of how different medial temporal lobe structures may contribute differently to memory functions.

Medications, psychotherapy, and other treatments are effective for many patients with psychiatric disorders. However, with currently available interventions, a substantial number of patients experience incomplete resolution of symptoms, and relapse rates are high. In the search for better treatments, increasing interest has focused on focal neuromodulation. This focus has been driven by improved neuroanatomical models of mood, thought, and behavior regulation, as well as by more advanced strategies for directly and focally altering neural activity. Deep brain stimulation (DBS) is one of the most invasive focal neuromodulation techniques available; data have supported its safety and efficacy in a number of movement disorders. Investigators have produced preliminary data on the safety and efficacy of DBS for several psychiatric disorders, as well. In this review, we describe the development and justification for testing DBS for various psychiatric disorders, carefully consider the available clinical data, and briefly discuss potential mechanisms of action.

Much of the central nervous system is involved in visuomotor transformations for goal-directed gaze and reach movements. These transformations are often described in terms of stimulus location, gaze fixation, and reach endpoints, as viewed through the lens of translational geometry. Here, we argue that the intrinsic (primarily rotational) 3-D geometry of the eye-head-reach systems determines the spatial relationship between extrinsic goals and effector commands, and therefore the required transformations. This approach provides a common theoretical framework for understanding both gaze and reach control. Combined with an assessment of the behavioral, neurophysiological, imaging, and neuropsychological literature, this framework leads us to conclude that (a) the internal representation and updating of visual goals are dominated by gaze-centered mechanisms, but (b) these representations must then be transformed as a function of eye and head orientation signals into effector-specific 3-D movement commands.

Traditionally the object of economic theory and experimental psychology, economic choice recently became a lively research focus in systems neuroscience. Here I summarize the emerging results and propose a unifying model of how economic choice might function at the neural level. Economic choice entails comparing options that vary on multiple dimensions. Hence, while choosing, individuals integrate different determinants into a subjective value; decisions are then made by comparing values. According to the good-based model, the values of different goods are computed independently of one another, which implies transitivity. Values are not learned as such, but rather computed at the time of choice. Most importantly, values are compared within the space of goods, independent of the sensorimotor contingencies of choice. Evidence from neurophysiology, imaging, and lesion studies indicates that abstract representations of value exist in the orbitofrontal and ventromedial prefrontal cortices. The computation and comparison of values may thus take place within these regions.

Depth structure, the third dimension of object shape, is extracted from disparity, motion, texture, and shading in the optic array. Gradient-selective neurons play a key role in this process. Such neurons occur in CIP, AIP, TEs, and F5 (for first- or second-order disparity gradients), in MT/V5, in FST (for speed gradients), and in CIP and TEs (for texture gradients). Most of these regions are activated during magnetic resonance scanning in alert monkeys by comparing 3D conditions with the 2D controls for the different cues. Similarities in activation patterns of monkeys and humans tested with identical paradigms suggest that like gradient-selective neurons are found in corresponding human cortical areas. This view gains credence as the homologies between such areas become more evident. Furthermore, 3D shape-processing networks are similar in the two species, with the exception of the greater involvement of human posterior parietal cortex in the extraction of 3D shape from motion. Thus we can begin to understand how depth structure is extracted from motion, disparity, and texture in the primate brain, but the extraction of depth structure from shading and that of wire-like objects requires further scrutiny.

Genetically encoded, single-component optogenetic tools have made a significant impact on neuroscience, enabling specific modulation of selected cells within complex neural tissues. As the optogenetic toolbox contents grow and diversify, the opportunities for neuroscience continue to grow. In this review, we outline the development of currently available single-component optogenetic tools and summarize the application of various optogenetic tools in diverse model organisms.

After spinal cord injury (SCI), various sensorimotor functions can recover, ranging from simple spinal reflexes to more elaborate motor patterns, such as locomotion. Locomotor recovery after complete spinalization (complete SCI) must depend on the presence of spinal circuitry capable of generating the complex sequential activation of various leg muscles. This is achieved by an intrinsic spinal circuitry, termed the central pattern generator (CPG), working in conjunction with sensory feedback from the legs. After SCI, different changes in cellular and circuit properties occur spontaneously and can be promoted by pharmacological, electrical, or rehabilitation strategies. After partial SCI, hindlimb locomotor recovery can result from regeneration or sprouting of spared pathways, but also from mechanisms observed after complete SCI, namely changes within the intrinsic spinal circuitry and sensory inputs.

The basal ganglia are a chain of subcortical nuclei that facilitate action selection. Two striatal projection systems—so-called direct and indirect pathways—form the functional backbone of the basal ganglia circuit. Twenty years ago, investigators proposed that the striatum's ability to use dopamine (DA) rise and fall to control action selection was due to the segregation of D1 and D2 DA receptors in direct- and indirect-pathway spiny projection neurons. Although this hypothesis sparked a debate, the evidence that has accumulated since then clearly supports this model. Recent advances in the means of marking neural circuits with optical or molecular reporters have revealed a clear-cut dichotomy between these two cell types at the molecular, anatomical, and physiological levels. The contrast provided by these studies has provided new insights into how the striatum responds to fluctuations in DA signaling and how diseases that alter this signaling change striatal function.

Odor signals received by odorant receptors (ORs) expressed by olfactory sensory neurons (OSNs) in the olfactory epithelium (OE) are represented as an odor map in the olfactory bulb (OB). In the mouse, there are ∼1,000 different OR species, and each OSN expresses only one functional OR gene in a monoallelic manner. Furthermore, OSN axons expressing the same type of OR converge on a specific target site in the OB, forming a glomerular structure. Because each glomerulus represents a single OR species, and a single odorant can interact with multiple OR species, odor signals received in the OE are converted into a topographic map of multiple glomeruli activated with varying magnitudes. Here we review recent progress in the study of the mammalian olfactory system, focusing on the formation of the olfactory map and the transmission of topographical information in the OB to the olfactory cortex to elicit various behaviors.