Annual Review of Neuroscience - Volume 33, 2010

For many years there has been a debate about the role of the parietal lobe in the generation of behavior. Does it generate movement plans (intention) or choose objects in the environment for further processing? To answer this, we focus on the lateral intraparietal area (LIP), an area that has been shown to play independent roles in target selection for saccades and the generation of visual attention. Based on results from a variety of tasks, we propose that LIP acts as a priority map in which objects are represented by activity proportional to their behavioral priority. We present evidence to show that the priority map combines bottom-up inputs like a rapid visual response with an array of top-down signals like a saccade plan. The spatial location representing the peak of the map is used by the oculomotor system to target saccades and by the visual system to guide visual attention.

The developing mammalian cerebral cortex contains a distinct class of cells, subplate neurons (SPns), that play an important role during early development. SPns are the first neurons to be generated in the cerebral cortex, they reside in the cortical white matter, and they are the first to mature physiologically. SPns receive thalamic and neuromodulatory inputs and project into the developing cortical plate, mostly to layer 4. Thus SPns form one of the first functional cortical circuits and are required to relay early oscillatory activity into the developing cortical plate. Pathophysiological impairment or removal of SPns profoundly affects functional cortical development. SPn removal in visual cortex prevents the maturation of thalamocortical synapses, the maturation of inhibition in layer 4, the development of orientation selective responses and the formation of ocular dominance columns. SPn removal also alters ocular dominance plasticity during the critical period. Therefore, SPns are a key regulator of cortical development and plasticity. SPns are vulnerable to injury during prenatal stages and might provide a crucial link between brain injury in development and later cognitive malfunction.

Fly motion vision and resultant compensatory optomotor responses are a classic example for neural computation. Here we review our current understanding of processing of optic flow as generated by an animal's self-motion. Optic flow processing is accomplished in a series of steps: First, the time-varying photoreceptor signals are fed into a two-dimensional array of Reichardt-type elementary motion detectors (EMDs). EMDs compute, in parallel, local motion vectors at each sampling point in space. Second, the output signals of many EMDs are spatially integrated on the dendrites of large-field tangential cells in the lobula plate. In the third step, tangential cells form extensive interactions with each other, giving rise to their large and complex receptive fields. Thus, tangential cells can act as matched filters tuned to optic flow during particular flight maneuvers. They finally distribute their information onto postsynaptic descending neurons, which either instruct the motor centers of the thoracic ganglion for flight and locomotion control or act themselves as motor neurons that control neck muscles for head movements.

Frontotemporal lobar degeneration (FTLD) is a neurodegenerative condition that predominantly affects behavior, social awareness, and language. It is characterized by extensive heterogeneity at the clinical, pathological, and genetic levels. Recognition of these levels of heterogeneity is important for proper disease management. The identification of progranulin and TDP-43 as key proteins in a significant proportion of FTLD patients has provided the impetus for a wealth of studies probing their role in neurodegeneration. This review highlights the most recent developments and future directions in this field and puts them in perspective of the novel insights into the neurodegenerative process, which have been gained from related disorders, e.g., the role of FUS in amyotrophic lateral sclerosis.

Motor control is the study of how organisms make accurate goal-directed movements. Here we consider two problems that the motor system must solve in order to achieve such control. The first problem is that sensory feedback is noisy and delayed, which can make movements inaccurate and unstable. The second problem is that the relationship between a motor command and the movement it produces is variable, as the body and the environment can both change. A solution is to build adaptive internal models of the body and the world. The predictions of these internal models, called forward models because they transform motor commands into sensory consequences, can be used to both produce a lifetime of calibrated movements, and to improve the ability of the sensory system to estimate the state of the body and the world around it. Forward models are only useful if they produce unbiased predictions. Evidence shows that forward models remain calibrated through motor adaptation: learning driven by sensory prediction errors.

Although there is no clear concept of volition or the will, we do have intuitive ideas that characterize the will, agency, and voluntary behavior. Here I review results from a number of strands of neuroscientific research that bear upon our intuitive notions of the will. These neuroscientific results provide some insight into the neural circuits mediating behaviors that we identify as related to will and volition. Although some researchers contend that neuroscience will undermine our views about free will, to date no results have succeeded in fundamentally disrupting our commonsensical beliefs. Still, the picture emerging from neuroscience does raise new questions, and ultimately may put pressure on some intuitive notions about what is necessary for free will.

Although the lifelong addition of new neurons to the olfactory bulb and dentate gyrus of mammalian brains is by now an accepted fact, the function of adult-generated neurons still largely remains a mystery. The ability of new neurons to form synapses with preexisting neurons without disrupting circuit function is central to the hypothesized role of adult neurogenesis as a substrate for learning and memory. With the development of several new genetic labeling and imaging techniques, the study of synapse development and integration of these new neurons into mature circuits both in vitro and in vivo is rapidly advancing our insight into their structural plasticity. Investigators' observation of synaptogenesis occurring in the adult brain is beginning to shed light on the flexibility that adult neurogenesis offers to mature circuits and the potential contribution of the transient plasticity that new neurons provide toward circuit refinement and adaptation to changing environmental demands.

Inherited ion channel mutations can affect the entire nervous system. Many cause paroxysmal disturbances of brain, spinal cord, peripheral nerve or skeletal muscle function, with normal neurological development and function in between attacks. To fully understand how mutations of ion channel genes cause disease, we need to know the normal location and function of the channel subunit, consequences of the mutation for biogenesis and biophysical properties, and possible compensatory changes in other channels that contribute to cell or circuit excitability. Animal models of monogenic channelopathies increasingly help our understanding. An important challenge for the future is to determine how more subtle derangements of ion channel function, which arise from the interaction of genetic and environmental influences, contribute to common paroxysomal disorders, including idiopathic epilepsy and migraine, that share features with rare monogenic channelopathies.

Neuroscientists have often described cognition and emotion as separable processes implemented by different regions of the brain, such as the amygdala for emotion and the prefrontal cortex for cognition. In this framework, functional interactions between the amygdala and prefrontal cortex mediate emotional influences on cognitive processes such as decision-making, as well as the cognitive regulation of emotion. However, neurons in these structures often have entangled representations, whereby single neurons encode multiple cognitive and emotional variables. Here we review studies using anatomical, lesion, and neurophysiological approaches to investigate the representation and utilization of cognitive and emotional parameters. We propose that these mental state parameters are inextricably linked and represented in dynamic neural networks composed of interconnected prefrontal and limbic brain structures. Future theoretical and experimental work is required to understand how these mental state representations form and how shifts between mental states occur, a critical feature of adaptive cognitive and emotional behavior.

The ability to group items and events into functional categories is a fundamental characteristic of sophisticated thought. It is subserved by plasticity in many neural systems, including neocortical regions (sensory, prefrontal, parietal, and motor cortex), the medial temporal lobe, the basal ganglia, and midbrain dopaminergic systems. These systems interact during category learning. Corticostriatal loops may mediate recursive, bootstrapping interactions between fast reward-gated plasticity in the basal ganglia and slow reward-shaded plasticity in the cortex. This can provide a balance between acquisition of details of experiences and generalization across them. Interactions between the corticostriatal loops can integrate perceptual, response, and feedback-related aspects of the task and mediate the shift from novice to skilled performance. The basal ganglia and medial temporal lobe interact competitively or cooperatively, depending on the demands of the learning task.

Neurofibromatosis Type I (NF1) is a single-gene disorder characterized by a high incidence of complex cognitive symptoms, including learning disabilities, attention deficit disorder, executive function deficits, and motor coordination problems. Because the underlying genetic cause of this disorder is known, study of NF1 from a molecular, cellular, and systems perspective has provided mechanistic insights into the etiology of higher-order cognitive symptoms associated with the disease. In particular, studies of animal models of NF1 indicated that disruption of Ras regulation of inhibitory networks is critical to the etiology of cognitive deficits associated with NF1. Animal models of Nf1 identified mechanisms and pathways that are required for cognition, and represent an important complement to the complex neuropsychological literature on learning disabilities associated with this condition. Here, we review findings from NF1 animal models and human populations affected by NF1, highlighting areas of potential translation and discussing the implications and limitations of generalizing findings from this single-gene disease to idiopathic learning disabilities.

Traditionally, researchers have believed that axons are highly dependent on their cell bodies for long-term survival. However, recent studies point to the existence of axon-autonomous mechanism(s) that regulate rapid axon degeneration after axotomy. Here, we review the cellular and molecular events that underlie this process, termed Wallerian degeneration. We describe the biphasic nature of axon degeneration after axotomy and our current understanding of how Wld^S—an extraordinary protein formed by fusing a Ube4b sequence to Nmnat1—acts to protect severed axons. Interestingly, the neuroprotective effects of Wld^S span all species tested, which suggests that there is an ancient, Wld^S-sensitive axon destruction program. Recent studies with Wld^S also reveal that Wallerian degeneration is genetically related to several dying back axonopathies, thus arguing that Wallerian degeneration can serve as a useful model to understand, and potentially treat, axon degeneration in diverse traumatic or disease contexts.

The neural bases of behavior are often discussed in terms of perceptual, cognitive, and motor stages, defined within an information processing framework that was originally inspired by models of human abstract problem solving. Here, we review a growing body of neurophysiological data that is difficult to reconcile with this influential theoretical perspective. As an alternative foundation for interpreting neural data, we consider frameworks borrowed from ethology, which emphasize the kinds of real-time interactive behaviors that animals have engaged in for millions of years. In particular, we discuss an ethologically-inspired view of interactive behavior as simultaneous processes that specify potential motor actions and select between them. We review how recent neurophysiological data from diverse cortical and subcortical regions appear more compatible with this parallel view than with the classical view of serial information processing stages.

Results from functional magnetic resonance imaging and lesion studies indicate that the prefrontal cortex (PFC) is essential for successful navigation through a complex social world inundated with intricate norms and moral values. This review examines regions of the PFC that are critical for implicit and explicit social cognitive and moral judgment processing. Considerable overlap between regions active when individuals engage in social cognition or assess moral appropriateness of behaviors is evident, underscoring the similarity between social cognitive and moral judgment processes in general. Findings are interpreted within the framework of structured event complex theory, providing a broad organizing perspective for how activity in PFC neural networks facilitates social cognition and moral judgment. We emphasize the dynamic flexibility in neural circuits involved in both implicit and explicit processing and discuss the likelihood that neural regions thought to uniquely underlie both processes heavily interact in response to different contextual primes.

Nociception is essential for survival whereas pathological pain is maladaptive and often unresponsive to pharmacotherapy. Voltage-gated sodium channels, Nav1.1–Nav1.9, are essential for generation and conduction of electrical impulses in excitable cells. Human and animal studies have identified several channels as pivotal for signal transmission along the pain axis, including Nav1.3, Nav1.7, Nav1.8, and Nav1.9, with the latter three preferentially expressed in peripheral sensory neurons and Nav1.3 being upregulated along pain-signaling pathways after nervous system injuries. Nav1.7 is of special interest because it has been linked to a spectrum of inherited human pain disorders. Here we review the contribution of these sodium channel isoforms to pain.

Emerging evidence indicates that once established, synapses and dendrites can be maintained for long periods, if not for the organism's entire lifetime. In contrast to the wealth of knowledge regarding axon, dendrite, and synapse development, we understand comparatively little about the cellular and molecular mechanisms that enable long-term synapse and dendrite maintenance. Here, we review how the actin cytoskeleton and its regulators, adhesion receptors, and scaffolding proteins mediate synapse and dendrite maintenance. We examine how these mechanisms are reinforced by trophic signals passed between the pre- and postsynaptic compartments. We also discuss how synapse and dendrite maintenance mechanisms are compromised in psychiatric and neurodegenerative disorders.

The vascular and nervous systems share a common necessity of circuit formation to coordinate nutrient and information transfer, respectively. Shared developmental principles have evolved to orchestrate the formation of both the vascular and the nervous systems. This evolution is highlighted by the identification of specific guidance cues that direct both systems to their target tissues. In addition to sharing cellular and molecular signaling events during development, the vascular and nervous systems also form an intricate interface within the central nervous system called the neurovascular unit. Understanding how the neurovascular unit develops and functions, and more specifically how the blood-brain barrier within this unit is established, is of utmost importance. We explore the history, recent discoveries, and unanswered questions surrounding the relationship between the vascular and nervous systems with a focus on developmental signaling cues that guide network formation and establish the interface between these two systems.

Although often considered as a group, spinal motor neurons are highly diverse in terms of their morphology, connectivity, and functional properties and differ significantly in their response to disease. Recent studies of motor neuron diversity have clarified developmental mechanisms and provided novel insights into neurodegeneration in amyotrophic lateral sclerosis (ALS). Motor neurons of different classes and subtypes—fast/slow, alpha/gamma—are grouped together into motor pools, each of which innervates a single skeletal muscle. Distinct mechanisms regulate their development. For example, glial cell line–derived neurotrophic factor (GDNF) has effects that are pool-specific on motor neuron connectivity, column-specific on axonal growth, and subtype-specific on survival. In multiple degenerative contexts including ALS, spinal muscular atrophy (SMA), and aging, fast-fatigable (FF) motor units degenerate early, whereas motor neurons innervating slow muscles and those involved in eye movement and pelvic sphincter control are strikingly preserved. Extrinsic and intrinsic mechanisms that confer resistance represent promising therapeutic targets in these currently incurable diseases.

The association of more than 140 genes with human photoreceptor degenerations, together with studies of animal models of these monogenic diseases, has provided great insight into their pathogenesis. Here we review the responses of the retina to photoreceptor mutations, including mechanisms of photoreceptor death. We discuss the roles of oxidative metabolism, mitochondrial reactive oxygen species, metabolic stress, protein misfolding, and defects in ciliary proteins, as well as the responses of Müller glia, microglia, and the retinal vasculature. Finally, we report on potential pharmacologic and biologic therapies, the critical role of histopathology as a prerequisite to treatment, and the exciting promise of gene therapy in animal models and in phase 1 trials in humans.

The assembly of specific synaptic connections during development of the nervous system represents a remarkable example of cellular recognition and differentiation. Neurons employ several different cellular signaling strategies to solve this puzzle, which successively limit unwanted interactions and reduce the number of direct recognition events that are required to result in a specific connectivity pattern. Specificity mechanisms include the action of contact-mediated and long-range signals that support or inhibit synapse formation, which can take place directly between synaptic partners or with transient partners and transient cell populations. The molecular signals that drive the synaptic differentiation process at individual synapses in the central nervous system are similarly diverse and act through multiple, parallel differentiation pathways. This molecular complexity balances the need for central circuits to be assembled with high accuracy during development while retaining plasticity for local and dynamic regulation.