A sizable body of evidence has shown that the brain computes several types of value-related signals to guide decision making, such as stimulus values, outcome values, and prediction errors. A critical question for understanding decision-making mechanisms is whether these value signals are computed using an absolute or a normalized code. Under an absolute code, the neural response used to represent the value of a given stimulus does not depend on what other values might have been encountered. By contrast, under a normalized code, the neural response associated with a given value depends on its relative position in the distribution of values. This review provides a simple framework for thinking about value normalization, and uses it to evaluate the existing experimental evidence.
Pitch perception is crucial for vocal communication, music perception, and auditory object processing in a complex acoustic environment. The neural representation of pitch in the cerebral cortex has long been an outstanding question in auditory neuroscience. Several lines of evidence now point to a distinct non-primary region of auditory cortex in primates that contains a cortical representation of pitch.
Williams syndrome (WS) offers an exciting model for social neuroscience because its genetic basis is well-defined, and the unique phenotype reflects dimensions of prosocial behaviors. WS is associated with a strong drive to approach strangers, a gregarious personality, heightened social engagement yet difficult peer interactions, high non-social anxiety, unusual bias toward positive affect, and diminished sensitivity to fear. New neurobiological evidence points toward alterations in structure, function, and connectivity of the social brain (amygdala, fusiform face area, orbital-frontal regions). Recent genetic studies implicate gene networks in the WS region with the dysregulation of prosocial neuropeptides. The study of WS has implications for understanding human social development, and may provide insight for translating genetic and neuroendocrine evidence into treatments for disorders of social behavior.
Auditory cortical maps have been a long-standing focus of studies that assess the expression, mechanisms, and consequences of sensory plasticity. Here we discuss recent progress in understanding how auditory experience transforms spatially organized sound representations at higher levels of the central auditory pathways. New insights into the mechanisms underlying map changes have been achieved and more refined interpretations of various map plasticity effects and their consequences in terms of behavioral corollaries and learning as well as other cognitive aspects have been offered. The systematic organizational principles of cortical sound processing remains a key-aspect in studying and interpreting the role of plasticity in hearing.
Dendritic spines are small mushroom-like protrusions arising from neurons where most excitatory synapses reside. Their peculiar shape suggests that spines can serve as an autonomous postsynaptic compartment that isolates chemical and electrical signaling. How neuronal activity modifies the morphology of the spine and how these modifications affect synaptic transmission and plasticity are intriguing issues. Indeed, the induction of long-term potentiation (LTP) or depression (LTD) is associated with the enlargement or shrinkage of the spine, respectively. This structural plasticity is mainly controlled by actin filaments, the principal cytoskeletal component of the spine. Here we review the pioneering microscopic studies examining the structural plasticity of spines and propose how changes in actin treadmilling might regulate spine morphology.
Obstructive sleep apnea (OSA) is a disorder of repetitive sleep disruption caused by reduced or blocked respiratory airflow. Although an anatomically compromised airway accounts for the major predisposition to OSA, a patient's arousal threshold and factors related to the central control of breathing (ventilatory control stability) are also important. Arousal from sleep (defined by EEG desynchronization) may be the only mechanism that allows airway re-opening following an obstructive event. However, in many cases arousal is unnecessary and even worsens the severity of OSA. Mechanisms for arousal are poorly understood. However, accumulating data are elucidating the relevant neural pathways and neurotransmitters. For example, serotonin is critically required, but its site of action is unknown. Important neural substrates for arousal have been recently identified in the parabrachial complex (PB), a visceral sensory nucleus in the rostral pons. Moreover, glutamatergic signaling from the PB contributes to arousal caused by hypercapnia, one of the arousal-promoting stimuli in OSA. A major current focus of OSA research is to find means to maintain airway patency during sleep, without sleep interruption.
Exosomes are small extracellular vesicles that mediate intercellular signaling in the brain without requiring direct contact between cells. Although exosomes have been shown to play a role in neurological diseases and in response to nerve trauma, a role for exosome-mediated signaling in brain development and function has not yet been demonstrated. Here we review data building a case for exosome function in the brain.
In peripheral nerves, Schwann cells form myelin, which facilitates the rapid conduction of action potentials along axons in the vertebrate nervous system. Myelinating Schwann cells are derived from neural crest progenitors in a step-wise process that is regulated by extracellular signals and transcription factors. In addition to forming the myelin sheath, Schwann cells orchestrate much of the regenerative response that occurs after injury to peripheral nerves. In response to injury, myelinating Schwann cells dedifferentiate into repair cells that are essential for axonal regeneration, and then redifferentiate into myelinating Schwann cells to restore nerve function. Although this remarkable plasticity has long been recognized, many questions remain unanswered regarding the signaling pathways regulating both myelination and the Schwann cell response to injury.
The proper function of the nervous system depends on precise production and connection of distinct neurons and glia. Cell fate determination of neurons and glia is tightly controlled by complex gene expression regulation in the developing and adult nervous system. Emerging evidence has demonstrated the importance of noncoding microRNAs (miRNAs) in neural development and function. This review highlights current discoveries of miRNA functions in specifying neuronal and glial cell fate. We summarize the roles of miRNAs in expansion and differentiation of neural stem cells, specification of neuronal subtypes and glial cells, reprogramming of functional neurons from embryonic stem cells and fibroblasts, and left-right asymmetric organization of neuronal subtypes. Investigating the network of interactions between miRNAs and target genes will reveal new gene regulation machinery involved in tuning the cell fate decisions of neurons and glia.
Despite their predominance in the nervous system, the precise ways in which glial cells develop and contribute to overall neural function remain poorly defined in any organism. Investigations in simple model organisms have identified remarkable morphological, molecular, and functional similarities between invertebrate and vertebrate glial subtypes. Invertebrates like Drosophila and C. elegans offer an abundance of tools for in vivo genetic manipulation of single cells or whole populations of glia, ease of access to neural tissues throughout development, and the opportunity for forward genetic analysis of fundamental aspects of glial cell biology. These features suggest that invertebrate model systems have high potential for vastly improving the understanding of glial biology. This review highlights recent work in Drosophila and other invertebrates that reveal new insights into basic mechanisms involved in glial development.
Over the past decade, developmental neuroscience has been transformed by the widespread application of confocal and two-photon fluorescence microscopy. Even greater progress is imminent, as recent innovations in microscopy now enable imaging with increased depth, speed, and spatial resolution; reduced phototoxicity; and in some cases without external fluorescent probes. We discuss these new techniques and emphasize their dramatic impact on neurobiology, including the ability to image neurons at depths exceeding 1 mm, to observe neurodevelopment noninvasively throughout embryogenesis, and to visualize neuronal processes or structures that were previously too small or too difficult to target with conventional microscopy.
During development, the migration of specific neuronal subtypes is required for the correct establishment of neural circuits. In mice and zebrafish, facial branchiomotor (FBM) neurons undergo a tangential migration from rhombomere 4 caudally through the hindbrain. Recent advances in the field have capitalized on genetic studies in zebrafish and mouse, and high-resolution time-lapse imaging in zebrafish. Planar cell polarity signaling has emerged as a critical conserved factor in FBM neuron migration, functioning both within the neurons and their environment. In zebrafish, migration depends on specialized ‘pioneer’ neurons to lead follower FBM neurons through the hindbrain, and on interactions with structural components including pre-laid axon tracts and the basement membrane. Despite fundamental conservation, species-specific differences in migration mechanisms are being uncovered.
Nodes of Ranvier are specialized axonal domains formed in response to a glial signal. Recent research advances have revealed that both CNS and PNS nodes form by several overlapping molecular mechanisms. However, the precise nature of these mechanisms and the hierarchy existing between them is considerably different in CNS vs. PNS nodes. Namely, the Schwann cells of the PNS, which directly contact the nodal axolemma, secrete proteins that cluster axonodal components at the edges of the growing myelin segment. In contrast, the formation of CNS nodes, which are not contacted by the myelinating glia, is surprisingly similar to the assembly of the axon initial segment and depends largely on axonal diffusion barriers.
Proper circuit connectivity is critical for nervous system function. Connectivity derives from the interaction of two interdependent modules: synaptic specificity and synaptic assembly. Specificity involves both targeting of neurons to specific laminar regions and the formation of synapses onto defined subcellular areas. In this review, we focus discussion on recently elucidated molecular mechanisms that control synaptic specificity and link them to synapse assembly. We use these molecular pathways to underscore fundamental cell biological concepts that underpin, and help explain, the rules governing synaptic specificity.
In the developing nervous system, synaptic connections are formed in excess and must remodel to achieve the precise synaptic connectivity characteristic of the mature organism. Synaptic pruning is a developmental process in which subsets of synapses are eliminated while the remaining synapses are preserved and strengthened. Recent findings have demonstrated unexpected roles for glial cells in this developmental process. These data demonstrate that phagocytic glia engulf synaptic and/or axonal elements in the developing nervous system and disruptions in this process result in sustained deficits in synaptic connectivity. These new findings highlight the importance of glia for nervous system development and function and may shed new light on mechanisms underlying nervous system disease.
From their initial ingression into the neural tube to the established, adult vascular plexus, blood vessels within the CNS are truly unique. Covered by a virtually continuous layer of perivascular cells and astrocytic endfeet and connected by specialized cell-cell junctional contacts, mature CNS blood vessels simultaneously provide nutritive blood flow and protect the neural mileu from potentially disruptive or harmful molecules and cells flowing through the vessel lumen. In this review we will discuss how the CNS vasculature acquires blood-brain barrier (BBB) properties with a specific focus on recent work identifying the cell types and molecular pathways that orchestrate barriergenesis.
The basal ganglia (BG) act as a cohesive functional unit that regulates motor function, habit formation, and reward/addictive behaviors; but the debate has only recently started on how the BG maintain wakefulness and suppress sleep to achieve all these fundamental functions of the BG. Neurotoxic lesioning, pharmacological approaches, and the behavioral analyses of genetically modified animals revealed that the striatum and globus pallidus are important for the control of sleep and wakefulness. Here, we discuss anatomical and molecular mechanisms for sleep-wake regulation in the BG and propose a plausible model in which the nucleus accumbens integrates behavioral processes with wakefulness through adenosine and dopamine receptors.
indirect pathway; locomotion; caudate-putamen; caffeine; modafinil
The reciprocal interactions between sleep and immune function are well-studied. Insufficient sleep induces innate immune responses as evidenced by increased expression of pro-inflammatory mediators in the brain and periphery. Conversely, immune challenges upregulate immunomodulator expression, which alters central nervous system-mediated processes and behaviors, including sleep. Recent studies indicate that glial cells, namely microglia and astrocytes, are active contributors to sleep and immune system interactions. Evidence suggests glial regulation of these interactions is mediated, in part, by adenosine and adenosine 5′-triphosphate actions at purinergic type 1 and type 2 receptors. Furthermore, microglia and astrocytes may modulate declines in sleep-wake behavior and immunity observed in aging.
Lifestyles involving sleep deprivation are common, despite mounting evidence that both acute total sleep deprivation and chronically restricted sleep degrade neurobehavioral functions associated with arousal, attention, memory and state stability. Current research suggests dynamic differences in the way the central nervous system responds to acute versus chronic sleep restriction, which is reflected in new models of sleep-wake regulation. Chronic sleep restriction likely induces long-term neuromodulatory changes in brain physiology that could explain why recovery from it may require more time than from acute sleep loss. High intraclass correlations in neurobehavioral responses to sleep loss suggest that these trait-like differences are phenotypic and may include genetic components. Sleep deprivation induces changes in brain metabolism and neural activation that involve distributed networks and connectivity.
Caenorhabditis elegans is the simplest animal shown to sleep. It sleeps during lethargus, a larval transition stage. Behavior during lethargus has the sleep properties of a specific quiescent posture and elevated arousal threshold that are reversible to strong stimulation and of increased sleep drive following sleep deprivation. Genetic similarities between sleep regulation during C. elegans lethargus and sleep regulation in other animals point to a sleep state that was an evolutionarily ancestor to sleep both in C. elegans and other animals. Recent publications have shed light on key questions in sleep biology: (1) How is sleep regulated? (2) How is sensory information gated during sleep? (3) How is sleep homeostasis mediated? (4) What is the core function of sleep?
The biochemical basis of circadian timekeeping is best characterized in cyanobacteria. The structures of its key molecular players, KaiA, KaiB, and KaiC are known and these proteins can reconstitute a remarkable circadian oscillation in a test tube. KaiC is rhythmically phosphorylated and its phospho-status is a marker of circadian phase that regulates ATPase activity and the oscillating assembly of a nanomachine. Analyses of the nanomachines have revealed how their timing circuit is ratcheted to be unidirectional and how they stay in synch to ensure a robust oscillator. These insights are likely to elucidate circadian timekeeping in higher organisms, including how transcription and translation could appear to be a core circadian timer when the true pacemaker is an embedded biochemical oscillator.