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  • Shared Functions of Perirhinal and Parahippocampal Cortices: Implications for Cognitive Aging
    Trends Neurosci. (IF 11.124) Pub Date : 2018-03-16
    Sara N. Burke, Leslie S. Gaynor, Carol A. Barnes, Russell M. Bauer, Jennifer L. Bizon, Erik D. Roberson, Lee Ryan

    A predominant view of perirhinal cortex (PRC) and postrhinal/parahippocampal cortex (POR/PHC) function contends that these structures are tuned to represent objects and spatial information, respectively. However, known anatomical connectivity, together with recent electrophysiological, neuroimaging, and lesion data, indicate that both brain areas participate in spatial and nonspatial processing. Instead of content-based organization, the PRC and PHC/POR may participate in two computationally distinct cortical–hippocampal networks: one network that is tuned to process coarse information quickly, forming gist-like representations of scenes/environments, and a second network tuned to process information about the specific sensory details that are necessary for discrimination across sensory modalities. The available data suggest that the latter network may be more vulnerable in advanced age.

  • Neurophysiological Changes Measured Using Somatosensory Evoked Potentials
    Trends Neurosci. (IF 11.124) Pub Date : 2018-03-14
    Antonella Macerollo, Matt J.N. Brown, James M. Kilner, Robert Chen

    Measurements of somatosensory evoked potentials (SEPs), recorded using electroencephalography during different phases of movement, have been fundamental in understanding the neurophysiological changes related to motor control. SEP recordings have also been used to investigate adaptive plasticity changes in somatosensory processing related to active and observational motor learning tasks. Combining noninvasive brain stimulation with SEP recordings and intracranial SEP depth recordings, including recordings from deep brain stimulation electrodes, has been critical in identifying neural areas involved in specific temporal stages of somatosensory processing. Consequently, this fundamental information has furthered our understanding of the maladaptive plasticity changes related to pathophysiology of diseases characterized by abnormal movements, such as Parkinson’s disease, dystonia, and functional movement disorders.

  • Cell Replacement to Reverse Brain Aging: Challenges, Pitfalls, and Opportunities
    Trends Neurosci. (IF 11.124) Pub Date : 2018-03-13
    Jean M. Hébert, Jan Vijg

    Current antiaging strategies focusing on druggable targets have met with relatively limited success to date. Replacement of cells, tissues, and organs could provide an alternative means for targeting age-induced damage and potentially eliminating some of it. However, before this is a viable option, numerous challenges need to be addressed. Most notably, whether the brain, which defines our self-identity, is amenable to replacement therapies is unclear. Here, we consider whether progressive cell replacement is a potential approach to reverse brain aging without grossly altering function. We focus mainly on the neocortex, seat of our highest cognitive functions, because of abundant knowledge on neocortical development, plasticity, and how the neocortex can functionally incorporate new neurons. We outline the primary challenges for brain cell replacement, and key areas that require further investigation.

  • Neuronal Fat and Dendrite Morphogenesis: The Goldilocks Effect
    Trends Neurosci. (IF 11.124) Pub Date : 2018-03-13
    Lakshmi Sundararajan, David M. Miller III

    Two recent studies by Meltzer et al. and Ziegler et al. use Drosophila larvae to demonstrate that cell-autonomous regulation of lipid biosynthesis defines the complexity and function of highly branched nociceptive neurons. Their findings show that lipid biosynthesis in the neuron is fine-tuned for optimal dendrite morphology and sensitivity.

  • Chromatin Regulation of Neuronal Maturation and Plasticity
    Trends Neurosci. (IF 11.124) Pub Date : 2018-03-09
    David A. Gallegos, Urann Chan, Liang-Fu Chen, Anne E. West

    Neurons are dynamic cells that respond and adapt to stimuli throughout their long postmitotic lives. The structural and functional plasticity of neurons requires the regulated transcription of new gene products, and dysregulation of transcription in either the developing or adult brain impairs cognition. We discuss how mechanisms of chromatin regulation help to orchestrate the transcriptional programs that underlie the maturation of developing neurons and the plasticity of adult neurons. We review how chromatin regulation acts locally to modulate the expression of specific genes and more broadly to coordinate gene expression programs during transitions between cellular states. These data highlight the importance of epigenetic transcriptional mechanisms in postmitotic neurons. We suggest areas where emerging methods may advance understanding in the future.

  • Extranuclear SUMOylation in Neurons
    Trends Neurosci. (IF 11.124) Pub Date : 2018-03-09
    Jeremy M. Henley, Ruth E. Carmichael, Kevin A. Wilkinson

    Post-translational modification of substrate proteins by SUMO conjugation regulates a diverse array of cellular processes. While predominantly a nuclear protein modification, there is a growing appreciation that SUMOylation of proteins outside the nucleus plays direct roles in controlling synaptic transmission, neuronal excitability, and adaptive responses to cell stress. Furthermore, alterations in protein SUMOylation are observed in a wide range of neurological and neurodegenerative diseases, and several extranuclear disease-associated proteins have been shown to be directly SUMOylated. Here, focusing mainly on SUMOylation of synaptic and mitochondrial proteins, we outline recent developments and discoveries, and present our opinion as to the most exciting avenues for future research to define how SUMOylation of extranuclear proteins regulates neuronal and synaptic function.

  • How the Barn Owl Computes Auditory Space
    Trends Neurosci. (IF 11.124) Pub Date : 2018-02-27
    Benedikt Grothe

    In a series of seminal behavioral and electrophysiological experiments, Knudsen and Konishi studied the mechanisms of hearing. Their 1979 article showed how the barn owl utilizes unique anatomical features for creating a systematic internal representation of auditory space. This established the barn owl as a prime model for studying sensory systems.

  • The Memory Map of Visual Space
    Trends Neurosci. (IF 11.124) Pub Date : 2018-02-27
    Román Rossi-Pool, José Vergara, Ranulfo Romo

    A 1989 paper by Patricia Goldman-Rakic and colleagues reported that the prefrontal cortex coded the visual space during working memory. This landmark work not only offered a biological explanation for this cognitive function, but also opened up a wide field of research aimed at understanding the biological bases of various cognitive functions.

  • Building on a Solid Baseline: Anticipatory Biases in Attention
    Trends Neurosci. (IF 11.124) Pub Date : 2018-02-27
    Anna C. Nobre, John T. Serences

    A brain-imaging paper by Kastner and colleagues in 1999 was the first to demonstrate that merely focusing attention at a spatial location changed the baseline activity level in various regions of human visual cortex even before any stimuli appeared. The study provided a touchstone for investigating cognitive–sensory interactions and understanding the proactive endogenous signals that shape perception.

  • Cell Type-Specific Optogenetic Dissection of Brain Rhythms
    Trends Neurosci. (IF 11.124) Pub Date : 2018-02-27
    Hillel Adesnik

    A pair of 2009 papers by Cardin et al. and Sohal et al. marked a watershed moment as optogenetics exploded onto the scene of systems neuroscience. This pair of back-to-back papers in the June issue of Nature leveraged a powerful combination of the Cre/lox system, adeno-associated viral gene vectors, and optogenetics to re-examine the circuit basis of neuronal synchronization.

  • The Circuit Motif as a Conceptual Tool for Multilevel Neuroscience
    Trends Neurosci. (IF 11.124) Pub Date : 2018-02-27
    Oliver Braganza, Heinz Beck

    Modern neuroscientific techniques that specifically manipulate and measure neuronal activity in behaving animals now allow bridging of the gap from the cellular to the behavioral level. However, in doing so, they also pose new challenges. Research using incompletely defined manipulations in a high-dimensional space without clear hypotheses is likely to suffer from multiple well-known conceptual and statistical problems. In this context it is essential to develop hypotheses with testable implications across levels. Here we propose that a focus on circuit motifs can help achieve this goal. Viewing neural structures as an assembly of circuit motif building blocks is not new. However, recent tool advances have made it possible to extensively map, specifically manipulate, and quantitatively investigate circuit motifs and thereby reexamine their relevance to brain function.

  • cAMP, cGMP and Amyloid β: Three Ideal Partners for Memory Formation
    Trends Neurosci. (IF 11.124) Pub Date : 2018-02-28
    Roberta Ricciarelli, Ernesto Fedele

    cAMP and cGMP are well established second messengers required for long-term potentiation (LTP) and memory formation/consolidation. By contrast, amyloid β (Aβ), mostly known as one of the main culprits for Alzheimer’s disease (AD), has received relatively little attention in the context of plasticity and memory. Of note, however, low physiological concentrations of Aβ seem necessary for LTP induction and for memory formation. This should come as no surprise, since hormesis emerged as a central dogma in biology. Additionally, recent evidence indicates that Aβ is one of the downstream effectors for cAMP and cGMP to trigger synaptic plasticity and memory. We argue that these emerging findings depict a new scenario that should change the general view on the amyloidogenic pathway, and that could have significant implications for the understanding of AD and its pharmacological treatment in the future.

  • Long Road to Ruin: Noradrenergic Dysfunction in Neurodegenerative Disease
    Trends Neurosci. (IF 11.124) Pub Date : 2018-02-20
    David Weinshenker

    It has been known for decades that degeneration of the locus coeruleus (LC), the major noradrenergic nucleus in the brain, occurs in both Alzheimer’s disease (AD) and Parkinson’s disease (PD), but it was given scant attention. It is now recognized that hyperphosphorylated tau in the LC is the first detectable AD-like neuropathology in the human brain, α-synuclein inclusions in the LC represent an early step in PD, and experimental LC lesions exacerbate neuropathology and cognitive/behavioral deficits in animal models. The purpose of this review is to consider the causes and consequences of LC pathology, dysfunction, and degeneration, as well as their implications for early detection and treatment.

  • Flexible Neural Hardware Supports Dynamic Computations in Retina
    Trends Neurosci. (IF 11.124) Pub Date : 2018-02-14
    Michal Rivlin-Etzion, William N. Grimes, Fred Rieke

    The ability of the retina to adapt to changes in mean light intensity and contrast is well known. Classically, however, adaptation is thought to affect gain but not to change the visual modality encoded by a given type of retinal neuron. Recent findings reveal unexpected dynamic properties in mouse retinal neurons that challenge this view. Specifically, certain cell types change the visual modality they encode with variations in ambient illumination or following repetitive visual stimulation. These discoveries demonstrate that computations performed by retinal circuits with defined architecture can change with visual input. Moreover, they pose a major challenge for central circuits that must decode properties of the dynamic visual signal from retinal outputs.

  • Why Do Hearing Aids Fail to Restore Normal Auditory Perception?
    Trends Neurosci. (IF 11.124) Pub Date : 2018-02-12
    Nicholas A. Lesica

    Hearing loss is a widespread condition that is linked to declines in quality of life and mental health. Hearing aids remain the treatment of choice, but, unfortunately, even state-of-the-art devices provide only limited benefit for the perception of speech in noisy environments. While traditionally viewed primarily as a loss of sensitivity, hearing loss is also known to cause complex distortions of sound-evoked neural activity that cannot be corrected by amplification alone. This Opinion article describes the effects of hearing loss on neural activity to illustrate the reasons why current hearing aids are insufficient and to motivate the use of new technologies to explore directions for improving the next generation of devices.

  • Respiration-Entrained Brain Rhythms Are Global but Often Overlooked
    Trends Neurosci. (IF 11.124) Pub Date : 2018-02-09
    Adriano B.L. Tort, Jurij Brankačk, Andreas Draguhn

    We revisit recent evidence showing that nasal respiration entrains oscillations at the same frequency as breathing in several regions of the rodent brain. Moreover, respiration modulates the amplitude of a specific gamma sub-band (70–120 Hz), most prominently in frontal regions. Since rodents often breathe at delta and theta frequencies, we caution that previous studies on delta and theta power and their cross-regional synchrony, as well as on delta–gamma and theta–gamma coupling, may have detected the respiration-entrained rhythm and respiration–gamma coupling. We argue that the simultaneous tracking of respiration along with electrophysiological recordings is necessary to properly identify brain oscillations. We hypothesize that respiration-entrained oscillations aid long-range communication in the brain.

  • The Hippocampus: From Memory, to Map, to Memory Map
    Trends Neurosci. (IF 11.124) Pub Date : 2018-02-06
    Kate J. Jeffery

    The hippocampus is one of the brain’s great mysteries. Historically, theories of its function included emotion, response inhibition, general memory and spatial perception/learning, with memory versus space emerging as a particular focus of more recent debates. A 1978 paper by Olton and colleagues captured this dichotomy by exploiting their newly developed radial maze task to reveal a profound deficit in the ability of hippocampally lesioned rats to execute a spatial memory task. This finding supported the emerging spatial map theory of hippocampal function, and helped pave the way for the subsequent uncovering of an entire brain system linking space and memory.

  • Structural Identification of the Nicotinic Receptor Ion Channel
    Trends Neurosci. (IF 11.124) Pub Date : 2018-02-06
    Jean-Pierre Changeux

    The structural identification of the cationic channel of the acetylcholine nicotinic receptor involved its biochemical tagging by channel blockers, followed by site-directed mutagenesis analyses reported in two papers in 1988. The ion channel was demonstrated to be lined by the transmembrane segment MII, in which the binding sites of channel blockers are “framed” by anionic rings.

  • Discovery of Hypocretin/Orexin Ushers in a New Era of Sleep Research
    Trends Neurosci. (IF 11.124) Pub Date : 2018-02-06
    David A. Prober

    Prior to the 21st century, genetic mechanisms that regulate sleep were largely unknown. In 1998, de Lecea et al. [1] (Proc. Natl. Acad. Sci. U. S. A. 1998; 95:322–327) and Sakurai et al. [2] (Cell 1998; 92: 573–585) reported the discovery of a gene they named hypocretin and orexin, respectively, which led to a revolution in our understanding of genetic and neuronal mechanisms that regulate sleep.

  • MeCP2 as an Activator of Gene Expression
    Trends Neurosci. (IF 11.124) Pub Date : 2018-02-06
    Patricia M. Horvath, Lisa M. Monteggia

    Rett syndrome is a neurodevelopmental disorder that primarily affects females and is caused by mutations in the methyl-CpG-binding-protein 2 (MECP2) gene. Initially, MeCP2 had been shown to be a repressor of gene transcription. In their 2008 paper, Chahrour and colleagues (DOI: 10.1126/science.1153252) reported that MeCP2 could also function as a transcriptional activator.

  • Neural Correlates of Unconsciousness in Large-Scale Brain Networks
    Trends Neurosci. (IF 11.124) Pub Date : 2018-02-03
    George A. Mashour, Anthony G. Hudetz

    The biological basis of consciousness is one of the most challenging and fundamental questions in 21st century science. A related pursuit aims to identify the neural correlates and causes of unconsciousness. We review current trends in the investigation of physiological, pharmacological, and pathological states of unconsciousness at the level of large-scale functional brain networks. We focus on the roles of brain connectivity, repertoire, graph-theoretical techniques, and neural dynamics in understanding the functional brain disconnections and reduced complexity that appear to characterize these states. Persistent questions in the field, such as distinguishing true correlates, linking neural scales, and understanding differential recovery patterns, are also addressed.

  • The Many Worlds of Plasticity Rules
    Trends Neurosci. (IF 11.124) Pub Date : 2018-02-01
    Jackie Schiller, Shai Berlin, Dori Derdikman

    Two recent papers have tackled the fundamental questions of how place fields are formed in a new environment and what plasticity mechanisms contribute to this process. Bittner et al., in their recent publication, discovered a novel plasticity rule that, in contrast to previous rules, spans the behavioral, seconds-long, timescale. Sheffield et al. have monitored, for the first time, dendritic activity during place field formation, and show the emergence of spatially tuned local NMDA spikes in basal dendrites of CA1 neurons. Together, these papers suggest that multiple complementary dendritic plasticity mechanisms may contribute to place field formation in changing environmental contexts.

  • A Systematic Look at Environmental Modulation and Its Impact in Brain Development
    Trends Neurosci. (IF 11.124) Pub Date : 2017-11-08
    Alessandro Sale

    Several experimental procedures are currently used to investigate the impact of the environment on brain plasticity under physiological and pathological conditions. The available methodologies are aimed at obtaining global or specific reductions or intensifications of the stimuli, with initial standardization in animal models being paralleled by translational applications to humans. More procedures can be combined together or applied in series to obtain powerful experimental paradigms, and the choice of a given setting should take into account the specific genetic background, age, and phenotypic vulnerabilities of the target subjects. Sophisticated use of environmental manipulations can increase our knowledge of the mechanisms underlying experience-dependent plasticity, opening the way for new therapies for neurodevelopmental disorders, dysfunctions of plasticity, and brain aging.

  • Flexible Roles for Proteoglycan Sulfation and Receptor Signaling
    Trends Neurosci. (IF 11.124) Pub Date : 2017-11-14
    Panpan Yu, Craig S. Pearson, Herbert M. Geller

    Proteoglycans (PGs) in the extracellular matrix (ECM) play vital roles in axon growth and navigation, plasticity, and regeneration of injured neurons. Different classes of PGs may support or inhibit cell growth, and their functions are determined in part by highly specific structural features. Among these, the pattern of sulfation on the PG sugar chains is a paramount determinant of a diverse and flexible set of outcomes. Recent studies of PG sulfation illustrate the challenges of attributing biological actions to specific sulfation patterns, and suggest ways in which highly similar molecules may exert opposing effects on neurons. The receptors for PGs, which have yet to be fully characterized, display a similarly nuanced spectrum of effects. Different classes of PG function via overlapping families of receptors and signaling pathways. This enables them to control axon growth and guidance with remarkable specificity, but it poses challenges for determining the precise binding interactions and downstream effects of different PGs and their assorted sulfated epitopes. This review examines existing and emerging evidence for the roles of PG sulfation and receptor interactions in determining how these complex molecules influence neuronal development, growth, and function.

  • Predicting Age Using Neuroimaging: Innovative Brain Ageing Biomarkers
    Trends Neurosci. (IF 11.124) Pub Date : 2017-10-23
    James H. Cole, Katja Franke

    The brain changes as we age and these changes are associated with functional deterioration and neurodegenerative disease. It is vital that we better understand individual differences in the brain ageing process; hence, techniques for making individualised predictions of brain ageing have been developed. We present evidence supporting the use of neuroimaging-based ‘brain age’ as a biomarker of an individual’s brain health. Increasingly, research is showing how brain disease or poor physical health negatively impacts brain age. Importantly, recent evidence shows that having an ‘older’-appearing brain relates to advanced physiological and cognitive ageing and the risk of mortality. We discuss controversies surrounding brain age and highlight emerging trends such as the use of multimodality neuroimaging and the employment of ‘deep learning’ methods.

  • Rebalancing the Addicted Brain: Oxytocin Interference with the Neural Substrates of Addiction
    Trends Neurosci. (IF 11.124) Pub Date : 2017-11-08
    Michael T. Bowen, Inga D. Neumann

    Drugs that act on the brain oxytocin (OXT) system may provide a much-needed treatment breakthrough for substance-use disorders. Targeting the brain OXT system has the potential to treat addiction to all major classes of addictive substance and to intervene across all stages of the addiction cycle. Emerging evidence suggests that OXT is able to interfere with such a wide range of addictive behaviours for such a wide range of addictive substances by rebalancing core neural systems that become dysregulated over the course of addiction. By improving our understanding of these interactions between OXT and the neural substrates of addiction, we will not only improve our understanding of addiction, but also our ability to effectively treat these devastating disorders.

  • Making Dopamine Connections in Adolescence
    Trends Neurosci. (IF 11.124) Pub Date : 2017-10-09
    Daniel Hoops, Cecilia Flores

    A dramatic maturational process ongoing in adolescence is prefrontal cortex development, including its dopamine innervation. Dopamine axons grow from the striatum to the prefrontal cortex, the only known case of long-distance axon growth during adolescence. This is coordinated by the Netrin-1 guidance cue receptor DCC (deleted in colorectal cancer), which in turn controls the intrinsic development of the prefrontal cortex itself. Stimulant drugs in adolescence alter DCC in dopamine neurons and, in turn prefrontal cortex maturation, impacting cognitive abilities. Variations in DCC expression are linked to psychiatric conditions of prefrontal cortex dysfunction, and microRNA regulation of DCC may be key to determining adolescent vulnerability or resilience. Since early interventions are proving to effectively ameliorate disease outcome, the Netrin-1 system is a promising therapeutic target.

  • Emerging Roles of CREB-Regulated Transcription Coactivators in Brain Physiology and Pathology
    Trends Neurosci. (IF 11.124) Pub Date : 2017-10-30
    Carlos A. Saura, Jean-René Cardinaux

    The brain has the ability to sense, coordinate, and respond to environmental changes through biological processes involving activity-dependent gene expression. cAMP-response element binding protein (CREB)-regulated transcription coactivators (CRTCs) have recently emerged as novel transcriptional regulators of essential biological functions, while their deregulation is linked to age-related human diseases. In the brain, CRTCs are unique signaling factors that act as sensors and integrators of hormonal, metabolic, and neural signals contributing to brain plasticity and brain–body communication. In this review, we focus on the regulatory mechanisms and functions of CRTCs in brain metabolism, lifespan, circadian rhythm, and synaptic mechanisms underlying memory and emotion. We also discuss how CRTCs deregulation in cognitive and emotional disorders may provide the basis for potential clinical and therapeutic applications in neurodegenerative and psychiatric diseases.

  • Chandelier Cells Illuminate Inhibitory Control of Prefrontal–Amygdala Outputs
    Trends Neurosci. (IF 11.124) Pub Date : 2017-10-04
    Thomas F. Giustino, Stephen Maren

    Inhibitory interneurons comprise a diverse subpopulation of cells that are critical to circuit function. How distinct inhibitory microcircuits control long-range projections remains poorly understood. A recent study by Lu and colleagues uncovered a unidirectional microcircuit of prefrontal chandelier cells that preferentially innervate and suppress long-range amygdala-projecting pyramidal cells.

  • Self as Object: Emerging Trends in Self Research
    Trends Neurosci. (IF 11.124) Pub Date : 2017-10-05
    Jie Sui, Xiaosi Gu

    Self representation is fundamental to mental functions. While the self has mostly been studied in traditional psychophilosophical terms (‘self as subject’), recent laboratory work suggests that the self can be measured quantitatively by assessing biases towards self-associated stimuli (‘self as object’). Here, we summarize new quantitative paradigms for assessing the self, drawn from psychology, neuroeconomics, embodied cognition, and social neuroscience. We then propose a neural model of the self as an emerging property of interactions between a core ‘self network’ (e.g., medial prefrontal cortex; mPFC), a cognitive control network [e.g., dorsolateral (dl)PFC], and a salience network (e.g., insula). This framework not only represents a step forward in self research, but also has important clinical significance, resonating recent efforts in computational psychiatry.

  • Estradiol Membrane-Initiated Signaling in the Brain Mediates Reproduction
    Trends Neurosci. (IF 11.124) Pub Date : 2017-09-29
    Paul E. Micevych, Paul G. Mermelstein, Kevin Sinchak

    Over the past few years our understanding of estrogen signaling in the brain has expanded rapidly. Estrogens are synthesized in the periphery and in the brain, acting on multiple receptors to regulate gene transcription, neural function, and behavior. Various estrogen-sensitive signaling pathways often operate in concert within the same cell, increasing the complexity of the system. In females, estrogen concentrations fluctuate over the estrous/menstrual cycle, dynamically modulating estrogen receptor (ER) expression, activity, and trafficking. These dynamic changes influence multiple behaviors but are particularly important for reproduction. Using the female rodent model, we review our current understanding of estradiol signaling in the regulation of sexual receptivity.

  • Stress and Seizures: Space, Time and Hippocampal Circuits
    Trends Neurosci. (IF 11.124) Pub Date : 2017-09-12
    B.G. Gunn, T.Z. Baram

    Stress is a major trigger of seizures in people with epilepsy. Exposure to stress results in the release of several stress mediators throughout the brain, including the hippocampus, a region sensitive to stress and prone to seizures. Stress mediators interact with their respective receptors to produce distinct effects on the excitability of hippocampal neurons and networks. Crucially, these stress mediators and their actions exhibit unique spatiotemporal profiles, generating a complex combinatorial output with time- and space-dependent effects on hippocampal network excitability and seizure generation.

  • A Self-Killing Rabies Virus That Leaves a Trace on the DNA
    Trends Neurosci. (IF 11.124) Pub Date : 2017-09-07
    William Menegas, Naoshige Uchida, Mitsuko Watabe-Uchida

    Although modified rabies viruses have emerged as a powerful tool for tracing the inputs to genetically defined populations of neurons, the toxicity of the virus has limited its utility. A recent study employed a self-inactivating rabies (SiR) virus that enables recording or manipulation of targeted neurons for months.

  • Endosomal Traffic Jams Represent a Pathogenic Hub and Therapeutic Target in Alzheimer’s Disease
    Trends Neurosci. (IF 11.124) Pub Date : 2017-09-26
    Scott A. Small, Sabrina Simoes-Spassov, Richard Mayeux, Gregory A. Petsko

    While clues have existed that endosomal trafficking is associated with Alzheimer’s disease (AD), whether it plays a central role in the disease and if so how has remained unknown. Here we rely on recent genetic and cellular findings to construct a model proposing that traffic jams in the early endosome can act as an upstream pathogenic hub in AD. We also rely on an independent series of findings to suggest how the traffic jams can act as a unified mediator of downstream pathophysiology. The model predicts, therefore, that interventions designed to unjam the endosome carry high therapeutic promise.

  • Phantom Limbs, Neuroprosthetics, and the Developmental Origins of Embodiment
    Trends Neurosci. (IF 11.124) Pub Date : 2017-09-26
    Mark S. Blumberg, James C. Dooley

    Amputees who wish to rid themselves of a phantom limb must weaken the neural representation of the absent limb. Conversely, amputees who wish to replace a lost limb must assimilate a neuroprosthetic with the existing neural representation. Whether we wish to remove a phantom limb or assimilate a synthetic one, we will benefit from knowing more about the developmental process that enables embodiment. A potentially critical contributor to that process is the spontaneous activity – in the form of limb twitches – that occurs exclusively and abundantly during active (REM) sleep, a particularly prominent state in early development. The sensorimotor circuits activated by twitching limbs, and the developmental context in which activation occurs, could provide a roadmap for creating neuroprosthetics that feel as if they are part of the body.

  • Cellular Computations Underlying Detection of Gaps in Sounds and Lateralizing Sound Sources
    Trends Neurosci. (IF 11.124) Pub Date : 2017-08-31
    Donata Oertel, Xiao-Jie Cao, James R. Ison, Paul D. Allen

    In mammals, acoustic information arises in the cochlea and is transmitted to the ventral cochlear nuclei (VCN). Three groups of VCN neurons extract different features from the firing of auditory nerve fibers and convey that information along separate pathways through the brainstem. Two of these pathways process temporal information: octopus cells detect coincident firing among auditory nerve fibers and transmit signals along monaural pathways, and bushy cells sharpen the encoding of fine structure and feed binaural pathways. The ability of these cells to signal with temporal precision depends on a low-voltage-activated K+ conductance (gKL) and a hyperpolarization-activated conductance (gh). This ‘tale of two conductances’ traces gap detection and sound lateralization to their cellular and biophysical origins.

  • The Brain Is Needed to Cure Spinal Cord Injury
    Trends Neurosci. (IF 11.124) Pub Date : 2017-09-08
    Tadashi Isa

    Damage to corticospinal fibers in the cervical spinal cord is known to impair dexterous hand movements. However, accumulating evidence has shown that precision grip can recover considerably through rehabilitative training. Recent multidisciplinary studies have revealed that, at the spinal level, this recovery is possible due to an indirect neural pathway through propriospinal neurons (PNs), which relay cortical commands to hand motoneurons. Although this indirect spinal pathway is heavily involved in recovery, its role is dwarfed by a simultaneous large-scale network reorganization spanning motor-related cortices and mesolimbic structures. This large-scale network reorganization is key to the regulation of recovery and future therapeutic strategies will need to take into account the involvement of these supraspinal centers in addition to the known role of the spinal cord.

  • Cholinergic Control of Information Coding
    Trends Neurosci. (IF 11.124) Pub Date : 2017-07-07
    Jochem van Kempen, Stefano Panzeri, Alexander Thiele

    Specific forms of firing rate correlations can limit efficient information coding in neuronal populations. How this is mitigated is an important topic of current research. A novel study shows that increasing cortical acetylcholine (ACh) levels alter specific aspects of the population correlation structure, which in turn improves population-coding abilities.

  • Acute or Chronic? A Stressful Question
    Trends Neurosci. (IF 11.124) Pub Date : 2017-08-01
    Laura Musazzi, Paolo Tornese, Nathalie Sala, Maurizio Popoli

    Stress is a primary risk factor for neuropsychiatric disorders; at times, even a single trauma can trigger psychopathology. Many rodent models of neuropsychiatric disorders use chronic stress, measuring readouts at the end of long protocols. In a way, traditional chronic models overlook a crucial question: how does the physiological response to stressor(s) turn into a maladaptive pathway that may verge towards psychopathology? Recent evidence suggests that studying the long-term consequences of acute stress would provide critical information on the role of stress in psychopathology. This new conceptual framework could enable us to understand the determinants of a pro-adaptive versus maladaptive trajectory of stress response, and also to study the mechanism of rapid-acting antidepressants, such as ketamine, that target the glutamate system directly.

  • NKCC1 Chloride Importer Antagonists Attenuate Many Neurological and Psychiatric Disorders
    Trends Neurosci. (IF 11.124) Pub Date : 2017-08-14
    Yehezkel Ben-Ari

    In physiological conditions, adult neurons have low intracellular Cl− [(Cl−)I] levels underlying the γ-aminobutyric acid (GABA)ergic inhibitory drive. In contrast, neurons have high (Cl−)I levels and excitatory GABA actions in a wide range of pathological conditions including spinal cord lesions, chronic pain, brain trauma, cerebrovascular infarcts, autism, Rett and Down syndrome, various types of epilepsies, and other genetic or environmental insults. The diuretic highly specific NKCC1 chloride importer antagonist bumetanide (PubChem CID: 2461) efficiently restores low (Cl−)I levels and attenuates many disorders in experimental conditions and in some clinical trials. Here, I review the mechanisms of action, therapeutic effects, promises, and pitfalls of bumetanide.

  • Seizing Control of KCC2: A New Therapeutic Target for Epilepsy
    Trends Neurosci. (IF 11.124) Pub Date : 2017-08-10
    Yvonne E. Moore, Matt R. Kelley, Nicholas J. Brandon, Tarek Z. Deeb, Stephen J. Moss

    Deficits in GABAergic inhibition result in the abnormal neuronal activation and synchronization that underlies seizures. However, the molecular mechanisms responsible for transforming a normal brain into an epileptic one remain largely unknown. Hyperpolarizing inhibition mediated by type A GABA (GABAA) receptors is dependent on chloride extrusion by the neuron-specific type 2 K+–Cl− cotransporter (KCC2). Loss-of-function mutations in KCC2 are a known cause of infantile epilepsy in humans and KCC2 dysfunction is present in patients with both idiopathic and acquired epilepsy. Here we discuss the growing evidence that KCC2 dysfunction has a central role in the development and severity of the epilepsies.

  • All Wrapped Up: Environmental Effects on Myelination
    Trends Neurosci. (IF 11.124) Pub Date : 2017-08-22
    Thomas A. Forbes, Vittorio Gallo

    To date, studies have demonstrated the dynamic influence of exogenous environmental stimuli on multiple regions of the brain. This environmental influence positively and negatively impacts programs governing myelination, and acts on myelinating oligodendrocyte (OL) cells across the human lifespan. Developmentally, environmental manipulation of OL progenitor cells (OPCs) has profound effects on the establishment of functional cognitive, sensory, and motor programs. Furthermore, central nervous system (CNS) myelin remains an adaptive entity in adulthood, sensitive to environmentally induced structural changes. Here, we discuss the role of environmental stimuli on mechanisms governing programs of CNS myelination under normal and pathological conditions. Importantly, we highlight how these extrinsic cues can influence the intrinsic power of myelin plasticity to promote functional recovery.

  • Renewed Attention on the Pupil Light Reflex
    Trends Neurosci. (IF 11.124) Pub Date : 2017-07-07
    Paola Binda, Paul D. Gamlin

    In a recent study, Ebitz and Moore described how subthreshold electrical microstimulation of the macaque frontal eye fields (FEF) modulates the pupillary light reflex. This elegant study suggests that the influence of the FEF and prefrontal cortex on attentional modulation of cortical visual processing extends to the subcortical circuit that mediates a very basic reflex, the pupillary light reflex.

  • Subcortical Contributions to Motor Speech: Phylogenetic, Developmental, Clinical
    Trends Neurosci. (IF 11.124) Pub Date : 2017-07-14
    W. Ziegler, H. Ackermann

    Vocal learning is an exclusively human trait among primates. However, songbirds demonstrate behavioral features resembling human speech learning. Two circuits have a preeminent role in this human behavior; namely, the corticostriatal and the cerebrocerebellar motor loops. While the striatal contribution can be traced back to the avian anterior forebrain pathway (AFP), the sensorimotor adaptation functions of the cerebellum appear to be human specific in acoustic communication. This review contributes to an ongoing discussion on how birdsong translates into human speech. While earlier approaches were focused on higher linguistic functions, we place the motor aspects of speaking at center stage. Genetic data are brought together with clinical and developmental evidence to outline the role of cerebrocerebellar and corticostriatal interactions in human speech.

  • Revolution of Resting-State Functional Neuroimaging Genetics in Alzheimer’s Disease
    Trends Neurosci. (IF 11.124) Pub Date : 2017-07-03
    Patrizia A. Chiesa, Enrica Cavedo, Simone Lista, Paul M. Thompson, Harald Hampel,

    The quest to comprehend genetic, biological, and symptomatic heterogeneity underlying Alzheimer’s disease (AD) requires a deep understanding of mechanisms affecting complex brain systems. Neuroimaging genetics is an emerging field that provides a powerful way to analyze and characterize intermediate biological phenotypes of AD. Here, we describe recent studies showing the differential effect of genetic risk factors for AD on brain functional connectivity in cognitively normal, preclinical, prodromal, and AD dementia individuals. Functional neuroimaging genetics holds particular promise for the characterization of preclinical populations; target populations for disease prevention and modification trials. To this end, we emphasize the need for a paradigm shift towards integrative disease modeling and neuroimaging biomarker-guided precision medicine for AD and other neurodegenerative diseases.

  • The Lateral Habenula and Adaptive Behaviors
    Trends Neurosci. (IF 11.124) Pub Date : 2017-07-05
    Sheri J.Y. Mizumori, Phillip M. Baker

    The evolutionarily conserved lateral habenula (LHb) enables dynamic responses to continually changing contexts and environmental conditions. A model is proposed to account for greater mnemonic and contextual control over LHb-mediated response flexibility as vertebrate brains became more complex. The medial prefrontal cortex (mPFC) provides instructions for context-specific responses to LHb, which assesses the extent to which this response information matches the motivation or internal state of the individual. LHb output either maintains a prior response (match) or leads to alternative responses (mismatch). It may also maintain current spatial and temporal processing in hippocampus (match), or alter such activity to reflect updated trajectory and sequenced information (mismatch). A response flexibility function of the LHb is consistent with poor behavioral control following its disruption (e.g., in depression).

  • Developmental Connectomics from Infancy through Early Childhood
    Trends Neurosci. (IF 11.124) Pub Date : 2017-07-03
    Miao Cao, Hao Huang, Yong He

    The human brain undergoes rapid growth in both structure and function from infancy through early childhood, and this significantly influences cognitive and behavioral development in later life. A newly emerging research framework, developmental connectomics, provides unprecedented opportunities for exploring the developing brain through non-invasive mapping of structural and functional connectivity patterns. Within this framework, we review recent neuroimaging and neurophysiological studies investigating connectome development from 20 postmenstrual weeks to 5 years of age. Specifically, we highlight five fundamental principles of brain network development during the critical first years of life, emphasizing strengthened segregation/integration balance, a remarkable hierarchical order from primary to higher-order regions, unparalleled structural and functional maturations, substantial individual variability, and high vulnerability to risk factors and developmental disorders.

  • Efficient Prevention of Neurodegenerative Diseases by Depletion of Starvation Response Factor Ataxin-2
    Trends Neurosci. (IF 11.124) Pub Date : 2017-07-03
    Georg Auburger, Nesli-Ece Sen, David Meierhofer, Ayşe-Nazlı Başak, Aaron D. Gitler

    Ataxin-2 (ATXN2) homologs exist in all eukaryotic organisms and may have contributed to their origin. Apart from a role in endocytosis, they are known for global effects on mRNA repair and ribosomal translation. Cell size, protein synthesis, and fat and glycogen storage are repressed by ATXN2 via mTORC1 signaling. However, specific liver mitochondrial matrix enzymes and the mitochondrial repair factor PINK1 require ATXN2 abundance. During periods of starvation, ATXN2 is transcriptionally induced and localized to cytosolic stress granules, where nuclear factors dock to compensate RNA pathology. These physiological actions were now revealed to be crucial for human neurodegenerative diseases, given that ATXN2 depletion is surprisingly efficient in preventing motor neuron and cerebellar atrophy, as demonstrated in mouse models, flies, and yeast.

  • Two sources of dopamine for the hippocampus
    Trends Neurosci. (IF 11.124) Pub Date : 2017-05-13
    Colin G. McNamara, David Dupret

    Dopaminergic signalling is established as playing an important role in novelty related modulation of hippocampal memory. Two recent studies have identified the noradrenergic fibres originating in the locus coeruleus as an additional source of neurotransmitter acting on dopaminergic receptors in the hippocampus.

  • Endocannabinoid Signaling in the Control of Social Behavior
    Trends Neurosci. (IF 11.124) Pub Date : 2017-05-26
    Don Wei, Stephen Allsop, Kay Tye, Daniele Piomelli

    Many mammalian species, including humans, exhibit social behavior and form complex social groups. Mechanistic studies in animal models have revealed important roles for the endocannabinoid signaling system, comprising G protein-coupled cannabinoid receptors and their endogenous lipid-derived agonists, in the control of neural processes that underpin social anxiety and social reward, two key aspects of social behavior. An emergent insight from these studies is that endocannabinoid signaling in specific circuits of the brain is context dependent and selectively recruited. These insights open new vistas on the neural basis of social behavior and social impairment.

  • The Role of Interneurons in Autism and Tourette Syndrome
    Trends Neurosci. (IF 11.124) Pub Date : 2017-05-31
    Maximiliano Rapanelli, Luciana Romina Frick, Christopher Pittenger

    The brain includes multiple types of interconnected excitatory and inhibitory neurons that together allow us to move, think, feel, and interact with the environment. Inhibitory interneurons (INs) comprise a small, heterogeneous fraction, but they exert a powerful and tight control over neuronal activity and consequently modulate the magnitude of neuronal output and, ultimately, information processing. IN abnormalities are linked to two pediatric psychiatric disorders with high comorbidity: autism spectrum disorder (ASD) and Tourette syndrome (TS). Studies probing the basis of this link have been contradictory regarding whether the causative mechanism is a reduction in number, dysfunction, or gene aberrant expression (or a combination thereof). Here, we integrate different theories into a more comprehensive view of INs as responsible for the symptomatology observed in these disorders.

  • Adaptive Capacity: An Evolutionary Neuroscience Model Linking Exercise, Cognition, and Brain Health
    Trends Neurosci. (IF 11.124) Pub Date : 2017-06-10
    David A. Raichlen, Gene E. Alexander

    The field of cognitive neuroscience was transformed by the discovery that exercise induces neurogenesis in the adult brain, with the potential to improve brain health and stave off the effects of neurodegenerative disease. However, the basic mechanisms underlying exercise–brain connections are not well understood. We use an evolutionary neuroscience approach to develop the adaptive capacity model (ACM), detailing how and why physical activity improves brain function based on an energy-minimizing strategy. Building on studies showing a combined benefit of exercise and cognitive challenge to enhance neuroplasticity, our ACM addresses two fundamental questions: (i) what are the proximate and ultimate mechanisms underlying age-related brain atrophy, and (ii) how do lifestyle changes influence the trajectory of healthy and pathological aging?

  • Mechanisms of Memory Disruption in Depression
    Trends Neurosci. (IF 11.124) Pub Date : 2018-01-10
    Daniel G. Dillon, Diego A. Pizzagalli

    Depressed individuals typically show poor memory for positive events, potentiated memory for negative events, and impaired recollection. These phenomena are clinically important but poorly understood. Compelling links between stress and depression suggest promising candidate mechanisms. Stress can suppress hippocampal neurogenesis, inhibit dopamine neurons, and sensitize the amygdala. We argue that these phenomena may impair pattern separation, disrupt the encoding of positive experiences, and bias retrieval toward negative events, respectively, thus recapitulating core aspects of memory disruption in depression. Encouragingly, optogenetic reactivation of cells engaged during the encoding of positive memories rapidly reduces depressive behavior in preclinical models. Thus, many memory deficits in depression appear to be downstream consequences of chronic stress, and addressing memory disruption can have therapeutic value.

  • Synaptic Tenacity or Lack Thereof: Spontaneous Remodeling of Synapses
    Trends Neurosci. (IF 11.124) Pub Date : 2017-12-21
    Noam E. Ziv, Naama Brenner

    Synaptic plasticity – the directed modulation of synaptic connections by specific activity histories or physiological signals – is believed to be a major mechanism for the modification of neuronal network function. This belief, however, has a ‘flip side’: the supposition that synapses do not change spontaneously in manners unrelated to such signals. Contrary to this supposition, recent studies reveal that synapses do change spontaneously, and to a fairly large extent. Here we review experimental results on spontaneous synaptic remodeling, its relative contributions to total synaptic remodeling, its statistical characteristics, and its physiological importance. We also address challenges it poses and avenues it opens for future experimental and theoretical research.

  • A Peek into Parkinson’s Disease Progression through Human Dopamine Neurons in a Dish
    Trends Neurosci. (IF 11.124) Pub Date : 2017-12-14
    Nan Yang, Zhenyu Yue

    Using induced human dopamine (DA) neurons, a study by Burbulla and colleagues demonstrated a toxic cascade of cellular dysfunctions which may underlie Parkinson’s disease (PD) progression. Their findings reveal what could be the causal relationship between multiple pathogenic pathways in human neurons obtained from idiopathic and familial cases, and suggest novel targets for therapeutic intervention.

  • Translational Control Mechanisms in Persistent Pain
    Trends Neurosci. (IF 11.124) Pub Date : 2017-12-14
    Arkady Khoutorsky, Theodore J. Price

    Persistent pain, which is poorly treated and estimated to afflict one third of the world’s population, is largely mediated by the sensitization of nociceptive neurons. This sensitization involves de novo gene expression to support biochemical and structural changes required to maintain amplified pain signaling that frequently persists even after injury to tissue resolves. While transcription-dependent changes in gene expression are important, recent work demonstrates that activity-dependent regulation of mRNA translation is key to controlling the cellular proteome and the development and maintenance of persistent pain. In this review, we highlight recent advances in translational regulation of gene expression in nociceptive circuits, with a focus on key signaling pathways and mRNA targets that may be tractable for the creation of next-generation pain therapeutics.

  • Structured Spontaneity: Building Circuits in the Human Prenatal Brain
    Trends Neurosci. (IF 11.124) Pub Date : 2017-12-07
    Moriah E. Thomason

    Early brain activity is crucial for neurogenesis and the development of brain networks. However, it has been challenging to localize regions in the developing human brain that contribute to spontaneous waves of neuronal activity. Recently, Arichi and colleagues reported that the temporal and heteromodal insular cortices have a central role in propagating these neural instructional signals.

  • Bioprinting for Neural Tissue Engineering
    Trends Neurosci. (IF 11.124) Pub Date : 2017-12-06
    Stephanie Knowlton, Shivesh Anand, Twisha Shah, Savas Tasoglu

    Bioprinting is a method by which a cell-encapsulating bioink is patterned to create complex tissue architectures. Given the potential impact of this technology on neural research, we review the current state-of-the-art approaches for bioprinting neural tissues. While 2D neural cultures are ubiquitous for studying neural cells, 3D cultures can more accurately replicate the microenvironment of neural tissues. By bioprinting neuronal constructs, one can precisely control the microenvironment by specifically formulating the bioink for neural tissues, and by spatially patterning cell types and scaffold properties in three dimensions. We review a range of bioprinted neural tissue models and discuss how they can be used to observe how neurons behave, understand disease processes, develop new therapies and, ultimately, design replacement tissues.

  • Polarity Sorting of Microtubules in the Axon
    Trends Neurosci. (IF 11.124) Pub Date : 2017-11-30
    Anand N. Rao, Peter W. Baas

    A longstanding question in cellular neuroscience is how microtubules in the axon become organized with their plus ends out, a pattern starkly different from the mixed orientation of microtubules in vertebrate dendrites. Recent attention has focused on a mechanism called polarity sorting, in which microtubules of opposite orientation are spatially separated by molecular motor proteins. Here we discuss this mechanism, and conclude that microtubules are polarity sorted in the axon by cytoplasmic dynein but that additional factors are also needed. In particular, computational modeling and experimental evidence suggest that static crosslinking proteins are required to appropriately restrict microtubule movements so that polarity sorting by cytoplasmic dynein can occur in a manner unimpeded by other motor proteins.

  • The Emerging Neurobiology of Bipolar Disorder
    Trends Neurosci. (IF 11.124) Pub Date : 2017-11-20
    Paul J. Harrison, John R. Geddes, Elizabeth M. Tunbridge

    Bipolar disorder (BD) is a leading cause of global disability. Its biological basis is unknown, and its treatment unsatisfactory. Here, we review two recent areas of progress. First, the discovery of risk genes and their implications, with a focus on voltage-gated calcium channels as part of the disease process and as a drug target. Second, facilitated by new technologies, it is increasingly apparent that the bipolar phenotype is more complex and nuanced than simply one of recurring manic and depressive episodes. One such feature is persistent mood instability, and efforts are underway to understand its mechanisms and its therapeutic potential. BD illustrates how psychiatry is being transformed by contemporary neuroscience, genomics, and digital approaches.

Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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