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Annual Review of Neuroscience [journal]
- Neural basis of the perception and estimation of time. [Journal Article, Review]
- Annu Rev Neurosci 2013 Jul 8.:313-36.
Understanding how sensory and motor processes are temporally integrated to control behavior in the hundredths of milliseconds-to-minutes range is a fascinating problem given that the basic electrophysiological properties of neurons operate on a millisecond timescale. Single-unit recording studies in monkeys have identified localized timing circuits, whereas neuropsychological studies of humans who have damage to the basal ganglia have indicated that core structures, such as the cortico-thalamic-basal ganglia circuit, play an important role in timing and time perception. Taken together, these data suggest that a core timing mechanism interacts with context-dependent areas. This idea of a temporal hub with a distributed network is used to investigate the abstract properties of interval tuning as well as temporal illusions and intersensory timing. We conclude by proposing that the interconnections built into this core timing mechanism are designed to provide a form of degeneracy as protection against injury, disease, or age-related decline.
- The genetics of hair cell development and regeneration. [Journal Article, Review]
- Annu Rev Neurosci 2013 Jul 8.:361-81.
Sensory hair cells are exquisitely sensitive vertebrate mechanoreceptors that mediate the senses of hearing and balance. Understanding the factors that regulate the development of these cells is important, not only to increase our understanding of ear development and its functional physiology but also to shed light on how these cells may be replaced therapeutically. In this review, we describe the signals and molecular mechanisms that initiate hair cell development in vertebrates, with particular emphasis on the transcription factor Atoh1, which is both necessary and sufficient for hair cell development. We then discuss recent findings on how microRNAs may modulate the formation and maturation of hair cells. Last, we review recent work on how hair cells are regenerated in many vertebrate groups and the factors that conspire to prevent this regeneration in mammals.
- Mechanisms and functions of theta rhythms. [Journal Article, Research Support, Non-U.S. Gov't, Review]
- Annu Rev Neurosci 2013 Jul 8.:295-312.
The theta rhythm is one of the largest and most sinusoidal activity patterns in the brain. Here I survey progress in the field of theta rhythms research. I present arguments supporting the hypothesis that theta rhythms emerge owing to intrinsic cellular properties yet can be entrained by several theta oscillators throughout the brain. I review behavioral correlates of theta rhythms and consider how these correlates inform our understanding of theta rhythms' functions. I discuss recent work suggesting that one function of theta is to package related information within individual theta cycles for more efficient spatial memory processing. Studies examining the role of theta phase precession in spatial memory, particularly sequence retrieval, are also summarized. Additionally, I discuss how interregional coupling of theta rhythms facilitates communication across brain regions. Finally, I conclude by summarizing how theta rhythms may support cognitive operations in the brain, including learning.
- Electrical compartmentalization in dendritic spines. [Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Review]
- Annu Rev Neurosci 2013 Jul 8.:429-49.
Most excitatory inputs in the CNS contact dendritic spines, avoiding dendritic shafts, so spines must play a key role for neurons. Recent data suggest that, in addition to enhancing connectivity and isolating synaptic biochemistry, spines can behave as electrical compartments independent from their parent dendrites. It is becoming clear that, although spines experience voltages similar to those of dendrites during action potentials (APs), spines must sustain higher depolarizations than do dendritic shafts during excitatory postsynaptic potentials (EPSPs). Synaptic potentials are likely amplified at the spine head and then reduced as they invade the dendrite through the spine neck. These electrical changes, probably due to a combination of passive and active mechanisms, may prevent the saturation of dendrites by the joint activation of many inputs, influence dendritic integration, and contribute to rapid synaptic plasticity. The electrical properties of spines could enable neural circuits to harness a high connectivity, implementing a "synaptic democracy," where each input can be individually integrated, tallied, and modified in order to generate emergent functional states.
- Transformation of visual signals by inhibitory interneurons in retinal circuits. [Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review]
- Annu Rev Neurosci 2013 Jul 8.:403-28.
One of the largest mysteries of the brain lies in understanding how higher-level computations are implemented by lower-level operations in neurons and synapses. In particular, in many brain regions inhibitory interneurons represent a diverse class of cells, the individual functional roles of which are unknown. We discuss here how the operations of inhibitory interneurons influence the behavior of a circuit, focusing on recent results in the vertebrate retina. A key role in this understanding is played by a common representation of the visual stimulus that can be applied at different stages. By considering how this stimulus representation changes at each location in the circuit, we can understand how neuron-level operations such as thresholds and inhibition yield circuit-level computations such as how stimulus selectivity and gain are controlled by local and peripheral visual stimuli.
- Gene therapy for blindness. [Journal Article, Review]
- Annu Rev Neurosci 2013 Jul 8.:467-88.
Sight-restoring therapy for the visually impaired and blind is a major unmet medical need. Ocular gene therapy is a rational choice for restoring vision or preventing the loss of vision because most blinding diseases originate in cellular components of the eye, a compartment that is optimally suited for the delivery of genes, and many of these diseases have a genetic origin or genetic component. In recent years we have witnessed major advances in the field of ocular gene therapy, and proof-of-concept studies are under way to evaluate the safety and efficacy of human gene therapies. Here we discuss the concepts and recent advances in gene therapy in the retina. Our review discusses traditional approaches such as gene replacement and neuroprotection and also new avenues such as optogenetic therapies. We conjecture that advances in gene therapy in the retina will pave the way for gene therapies in other parts of the brain.
- RNA protein interaction in neurons. [Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review]
- Annu Rev Neurosci 2013 Jul 8.:243-70.
Neurons have their own systems for regulating RNA. Several multigene families encode RNA binding proteins (RNABPs) that are uniquely expressed in neurons, including the well-known neuron-specific markers ELAV and NeuN and the disease antigen NOVA. New technologies have emerged in recent years to assess the function of these proteins in vivo, and the answers are yielding insights into how and why neurons may regulate RNA in special ways-to increase cellular complexity, to localize messenger RNA (mRNA) spatially, and to regulate their expression in response to synaptic stimuli. The functions of such restricted neuronal proteins are likely to be complemented by more widely expressed RNABPs that may themselves have developed specialized functions in neurons, including Argonaute/microRNAs (miRNAs). Here we review what is known about such RNABPs and explore the potential biologic and neurologic significance of neuronal RNA regulatory systems.
- From atomic structures to neuronal functions of g protein-coupled receptors. [Journal Article, Research Support, N.I.H., Extramural, Review]
- Annu Rev Neurosci 2013 Jul 8.:139-64.
G protein-coupled receptors (GPCRs) are essential mediators of signal transduction, neurotransmission, ion channel regulation, and other cellular events. GPCRs are activated by diverse stimuli, including light, enzymatic processing of their N-termini, and binding of proteins, peptides, or small molecules such as neurotransmitters. GPCR dysfunction caused by receptor mutations and environmental challenges contributes to many neurological diseases. Moreover, modern genetic technology has helped identify a rich array of mono- and multigenic defects in humans and animal models that connect such receptor dysfunction with disease affecting neuronal function. The visual system is especially suited to investigate GPCR structure and function because advanced imaging techniques permit structural studies of photoreceptor neurons at both macro and molecular levels that, together with biochemical and physiological assessment in animal models, provide a more complete understanding of GPCR signaling.
- Superior colliculus and visual spatial attention. [Journal Article, Review]
- Annu Rev Neurosci 2013 Jul 8.:165-82.
The superior colliculus (SC) has long been known to be part of the network of brain areas involved in spatial attention, but recent findings have dramatically refined our understanding of its functional role. The SC both implements the motor consequences of attention and plays a crucial role in the process of target selection that precedes movement. Moreover, even in the absence of overt orienting movements, SC activity is related to shifts of covert attention and is necessary for the normal control of spatial attention during perceptual judgments. The neuronal circuits that link the SC to spatial attention may include attention-related areas of the cerebral cortex, but recent results show that the SC's contribution involves mechanisms that operate independently of the established signatures of attention in visual cortex. These findings raise new issues and suggest novel possibilities for understanding the brain mechanisms that enable spatial attention.
- Genetic approaches to neural circuits in the mouse. [Journal Article, Review]
- Annu Rev Neurosci 2013 Jul 8.:183-215.
To understand the organization and assembly of mammalian brain circuits, we need a comprehensive tool set that can address the challenges of cellular diversity, spatial complexity at synapse resolution, dynamic complexity of circuit operations, and multifaceted developmental processes rooted in the genome. Complementary to physics- and chemistry-based methods, genetic tools tap into intrinsic cellular and developmental mechanisms. Thus, they have the potential to achieve appropriate spatiotemporal resolution and the cellular-molecular specificity necessary for observing and probing the makings and inner workings of neurons and neuronal circuits. Furthermore, genetic analysis will be key to unraveling the intricate link from genes to circuits to systems, in part through systematic targeting and tracking of individual cellular components of neural circuits. Here we review recent progress in genetic tool development and advances in genetic analysis of neural circuits in the mouse. We also discuss future directions and implications for understanding brain disorders.