Showing papers in "Nature Neuroscience in 2013"

Memory, navigation and theta rhythm in the hippocampal-entorhinal system

Abstract: In this review, Gyorgy Buzsaki and Edvard Moser discuss the most recent evidence suggesting that the navigation and memory functions of the hippocampus and entorhinal cortex are supported by the same neuronal algorithms. They propose that the mechanisms fueling the memory and mental travel engines in the hippocampal-entorhinal system evolved from the mechanisms supporting navigation in the physical world.

Multi-task connectivity reveals flexible hubs for adaptive task control

Abstract: Extensive evidence suggests that the human ability to adaptively implement a wide variety of tasks is preferentially a result of the operation of a fronto-parietal brain network (FPN). We hypothesized that this network's adaptability is made possible by flexible hubs: brain regions that rapidly update their pattern of global functional connectivity according to task demands. Using recent advances in characterizing brain network organization and dynamics, we identified mechanisms consistent with the flexible hub theory. We found that the FPN's brain-wide functional connectivity pattern shifted more than those of other networks across a variety of task states and that these connectivity patterns could be used to identify the current task. Furthermore, these patterns were consistent across practiced and novel tasks, suggesting that reuse of flexible hub connectivity patterns facilitates adaptive (novel) task performance. Together, these findings support a central role for fronto-parietal flexible hubs in cognitive control and adaptive implementation of task demands.

M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination

Abstract: In this study, the authors show that oligodendrocyte differentiation and remyelination after a CNS lesion coincides with a switch in microglial/macrophage polarization from a pro-inflammatory, M1, phenotype to an anti-inflammatory, M2, phenotype. This M2-dependant effect was in part mediated by secretion of the TGFβ family member, Activin-A.

Inhibition of Inhibition in Visual Cortex: The Logic of Connections Between Molecularly Distinct Interneurons

Abstract: Cortical inhibitory neurons contact each other to form a network of inhibitory synaptic connections. Our knowledge of the connectivity pattern underlying this inhibitory network is, however, still incomplete. Here we describe a simple and complementary interaction scheme between three large, molecularly distinct interneuron populations in mouse visual cortex: parvalbumin-expressing interneurons strongly inhibit one another but provide little inhibition to other populations. In contrast, somatostatin-expressing interneurons avoid inhibiting one another yet strongly inhibit all other populations. Finally, vasoactive intestinal peptide-expressing interneurons preferentially inhibit somatostatin-expressing interneurons. This scheme occurs in supragranular and infragranular layers, suggesting that inhibitory networks operate similarly at the input and output of the visual cortex. Thus, as the specificity of connections between excitatory neurons forms the basis for the cortical canonical circuit, the scheme described here outlines a standard connectivity pattern among cortical inhibitory neurons.

Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions

Abstract: Although the fact that genetic predisposition and environmental exposures interact to shape development and function of the human brain and, ultimately, the risk of psychiatric disorders has drawn wide interest, the corresponding molecular mechanisms have not yet been elucidated. We found that a functional polymorphism altering chromatin interaction between the transcription start site and long-range enhancers in the FK506 binding protein 5 (FKBP5) gene, an important regulator of the stress hormone system, increased the risk of developing stress-related psychiatric disorders in adulthood by allele-specific, childhood trauma-dependent DNA demethylation in functional glucocorticoid response elements of FKBP5. This demethylation was linked to increased stress-dependent gene transcription followed by a long-term dysregulation of the stress hormone system and a global effect on the function of immune cells and brain areas associated with stress regulation. This identification of molecular mechanisms of genotype-directed long-term environmental reactivity will be useful for designing more effective treatment strategies for stress-related disorders.

The microglial sensome revealed by direct RNA sequencing

Abstract: Microglia, the principal neuroimmune sentinels of the brain, continuously sense changes in their environment and respond to invading pathogens, toxins and cellular debris. Microglia exhibit plasticity and can assume neurotoxic or neuroprotective priming states that determine their responses to danger. We used direct RNA sequencing, without amplification or cDNA synthesis, to determine the quantitative transcriptomes of microglia of healthy adult and aged mice. We validated our findings by fluorescent dual in-situ hybridization, unbiased proteomic analysis and quantitative PCR. We report here that microglia have a distinct transcriptomic signature and express a unique cluster of transcripts encoding proteins for sensing endogenous ligands and microbes that we term the “sensome”. With aging, sensome transcripts for endogenous ligand recognition are downregulated, whereas those involved in microbe recognition and host defense are upregulated. In addition, aging is associated with an overall increase in expression of microglial genes involved in neuroprotection.

Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways

Abstract: Microglia are crucial for immune responses in the brain. Although their origin from the yolk sac has been recognized for some time, their precise precursors and the transcription program that is used are not known. We found that mouse microglia were derived from primitive c-kit(+) erythromyeloid precursors that were detected in the yolk sac as early as 8 d post conception. These precursors developed into CD45(+) c-kit(lo) CX(3)CR1(-) immature (A1) cells and matured into CD45(+) c-kit(-) CX(3)CR1(+) (A2) cells, as evidenced by the downregulation of CD31 and concomitant upregulation of F4/80 and macrophage colony stimulating factor receptor (MCSF-R). Proliferating A2 cells became microglia and invaded the developing brain using specific matrix metalloproteinases. Notably, microgliogenesis was not only dependent on the transcription factor Pu.1 (also known as Sfpi), but also required Irf8, which was vital for the development of the A2 population, whereas Myb, Id2, Batf3 and Klf4 were not required. Our data provide cellular and molecular insights into the origin and development of microglia.

Long-term dynamics of CA1 hippocampal place codes

Abstract: Using Ca(2+) imaging in freely behaving mice that repeatedly explored a familiar environment, we tracked thousands of CA1 pyramidal cells' place fields over weeks. Place coding was dynamic, as each day the ensemble representation of this environment involved a unique subset of cells. However, cells in the ∼15-25% overlap between any two of these subsets retained the same place fields, which sufficed to preserve an accurate spatial representation across weeks.

Opportunities and limitations of intrinsic functional connectivity MRI

Abstract: Intrinsic functional connectivity magnetic resonance imaging (fcMRI) has emerged as a powerful tool for mapping large-scale networks in the human brain. Robust and reliable functionally coupled networks can be detected in individuals that echo many known features of anatomical organization. Features of brain organization have been discovered, including descriptions of distributed large-scale networks interwoven throughout association cortex, interactions (including anticorrelations) between brain networks and insights into the topography of subcortical structures. But interpreting fcMRI is complicated by several factors. Functional coupling changes dynamically, suggesting that it is constrained by, but not fully dictated by, anatomic connectivity. Critically to study of between-group differences, fcMRI is sensitive to head motion and to differences in the mental states of participants during the scans. We discuss the potential of fcMRI in the context of its limitations.

SeeDB: a simple and morphology-preserving optical clearing agent for neuronal circuit reconstruction

Abstract: This technical report describes a method to clear fixed brain tissues while allowing for fluorescent dye tracing and retaining cellular morphology. The authors demonstrate the utility of the technique by obtaining a wiring diagram for sister mitral cells.

A causal link between prediction errors, dopamine neurons and learning

Abstract: Situations in which rewards are unexpectedly obtained or withheld represent opportunities for new learning. Often, this learning includes identifying cues that predict reward availability. Unexpected rewards strongly activate midbrain dopamine neurons. This phasic signal is proposed to support learning about antecedent cues by signaling discrepancies between actual and expected outcomes, termed a reward prediction error. However, it is unknown whether dopamine neuron prediction error signaling and cue-reward learning are causally linked. To test this hypothesis, we manipulated dopamine neuron activity in rats in two behavioral procedures, associative blocking and extinction, that illustrate the essential function of prediction errors in learning. We observed that optogenetic activation of dopamine neurons concurrent with reward delivery, mimicking a prediction error, was sufficient to cause long-lasting increases in cue-elicited reward-seeking behavior. Our findings establish a causal role for temporally precise dopamine neuron signaling in cue-reward learning, bridging a critical gap between experimental evidence and influential theoretical frameworks.

ReaChR: a red-shifted variant of channelrhodopsin enables deep transcranial optogenetic excitation

Abstract: Channelrhodopsins (ChRs) are used to optogenetically depolarize neurons. We engineered a variant of ChR, denoted red-activatable ChR (ReaChR), that is optimally excited with orange to red light (λ ∼590-630 nm) and offers improved membrane trafficking, higher photocurrents and faster kinetics compared to existing red-shifted ChRs. Red light is less scattered by tissue and is absorbed less by blood than the blue to green wavelengths that are required by other ChR variants. We used ReaChR expressed in the vibrissa motor cortex to drive spiking and vibrissa motion in awake mice when excited with red light through intact skull. Precise vibrissa movements were evoked by expressing ReaChR in the facial motor nucleus in the brainstem and illumination with red light through the external auditory canal. Thus, ReaChR enables transcranial optical activation of neurons in deep brain structures without the need to surgically thin the skull, form a transcranial window or implant optical fibers.

A disinhibitory circuit mediates motor integration in the somatosensory cortex

Abstract: The influence of motor activity on sensory processing is crucial for perception and motor execution. However, the underlying circuits are not known. To unravel the circuit by which activity in the primary vibrissal motor cortex (vM1) modulates sensory processing in the primary somatosensory barrel cortex (S1), we used optogenetics to examine the long-range inputs from vM1 to the various neuronal elements in S1. We found that S1-projecting vM1 pyramidal neurons strongly recruited vasointestinal peptide (VIP)-expressing GABAergic interneurons, a subset of serotonin receptor-expressing interneurons. These VIP interneurons preferentially inhibited somatostatin-expressing interneurons, neurons that target the distal dendrites of pyramidal cells. Consistent with this vM1-mediated disinhibitory circuit, the activity of VIP interneurons in vivo increased and that of somatostatin interneurons decreased during whisking. These changes in firing rates during whisking depended on vM1 activity. Our results suggest previously unknown circuitry by which inputs from motor cortex influence sensory processing in sensory cortex.

Oligodendrocyte progenitors balance growth with self-repulsion to achieve homeostasis in the adult brain.

Abstract: The adult CNS contains an abundant population of oligodendrocyte precursor cells (NG2(+) cells) that generate oligodendrocytes and repair myelin, but how these ubiquitous progenitors maintain their density is unknown. We generated NG2-mEGFP mice and used in vivo two-photon imaging to study their dynamics in the adult brain. Time-lapse imaging revealed that NG2(+) cells in the cortex were highly dynamic; they surveyed their local environment with motile filopodia, extended growth cones and continuously migrated. They maintained unique territories though self-avoidance, and NG2(+) cell loss though death, differentiation or ablation triggered rapid migration and proliferation of adjacent cells to restore their density. NG2(+) cells recruited to sites of focal CNS injury were similarly replaced by a proliferative burst surrounding the injury site. Thus, homeostatic control of NG2(+) cell density through a balance of active growth and self-repulsion ensures that these progenitors are available to replace oligodendrocytes and participate in tissue repair.

Probabilistic brains: knowns and unknowns

Abstract: There is strong behavioral and physiological evidence that the brain both represents probability distributions and performs probabilistic inference. Computational neuroscientists have started to shed light on how these probabilistic representations and computations might be implemented in neural circuits. One particularly appealing aspect of these theories is their generality: they can be used to model a wide range of tasks, from sensory processing to high-level cognition. To date, however, these theories have only been applied to very simple tasks. Here we discuss the challenges that will emerge as researchers start focusing their efforts on real-life computations, with a focus on probabilistic learning, structural learning and approximate inference.

Cellular mechanisms of brain state-dependent gain modulation in visual cortex.

Abstract: Visual cortical neurons fire at higher rates to visual stimuli during locomotion than during immobility, while maintaining orientation selectivity. The mechanisms underlying this change in gain are not understood. We performed whole-cell recordings from layer 2/3 and layer 4 visual cortical excitatory neurons and from parvalbumin-positive and somatostatin-positive inhibitory neurons in mice that were free to rest or run on a spherical treadmill. We found that the membrane potential of all cell types became more depolarized and (with the exception of somatostatin-positive interneurons) less variable during locomotion. Cholinergic input was essential for maintaining the unimodal membrane potential distribution during immobility, whereas noradrenergic input was necessary for the tonic depolarization associated with locomotion. Our results provide a mechanism for how neuromodulation controls the gain and signal-to-noise ratio of visual cortical neurons during changes in the state of vigilance.

Layer V cortical neurons require microglial support for survival during postnatal development

Abstract: Neurons require trophic support during neural circuit formation; however, how the cellular milieu contributes to neuronal survival remains unclear. We found that layer V cortical neurons require support from microglia for survival during postnatal development. Specifically, we found that microglia accumulated close to the subcerebral and callosal projection axons in the postnatal brain. Inactivation of microglia by minocycline treatment or transient ablation of microglia in CD11b-DTR transgenic mice led to increased apoptosis, specifically in layer V subcerebral and callosal projection neurons. CX3CR1 in microglia was required for the survival of layer V neurons. Microglia consistently promoted the survival of cortical neurons in vitro. In addition, we identified microglia-derived IGF1 as a trophic factor that maintained neuronal survival. Our results highlight a neuron-glia interaction that is indispensable for network formation during a specific period in the developing brain.

Sleep-dependent memory triage: evolving generalization through selective processing

Abstract: This Review article discusses in the context of learning and memory the function of sleep to earmark which daily event or information should be consolidated and which mundane information should be discarded, and how this 'memory triage' process is a selective and yet generalization process that can also bind features together in a non-congruous manner when they are recalled. The brain does not retain all the information it encodes in a day. Much is forgotten, and of those memories retained, their subsequent evolution can follow any of a number of pathways. Emerging data makes clear that sleep is a compelling candidate for performing many of these operations. But how does the sleeping brain know which information to preserve and which to forget? What should sleep do with that information it chooses to keep? For information that is retained, sleep can integrate it into existing memory networks, look for common patterns and distill overarching rules, or simply stabilize and strengthen the memory exactly as it was learned. We suggest such 'memory triage' lies at the heart of a sleep-dependent memory processing system that selects new information, in a discriminatory manner, and assimilates it into the brain's vast armamentarium of evolving knowledge, helping guide each organism through its own, unique life.

A new type of microglia gene targeting shows TAK1 to be pivotal in CNS autoimmune inflammation

Abstract: Microglia are brain macrophages and, as such, key immune-competent cells that can respond to environmental changes. Understanding the mechanisms of microglia-specific responses during pathologies is hence vital for reducing disease burden. The definition of microglial functions has so far been hampered by the lack of genetic in vivo approaches that allow discrimination of microglia from closely related peripheral macrophage populations in the body. Here we introduce a mouse experimental system that specifically targets microglia to examine the role of a mitogen-associated protein kinase kinase kinase (MAP3K), transforming growth factor (TGF)-β-activated kinase 1 (TAK1), during autoimmune inflammation. Conditional depletion of TAK1 in microglia only, not in neuroectodermal cells, suppressed disease, significantly reduced CNS inflammation and diminished axonal and myelin damage by cell-autonomous inhibition of the NF-κB, JNK and ERK1/2 pathways. Thus, we found TAK1 to be pivotal in CNS autoimmunity, and we present a tool for future investigations of microglial function in the CNS.

Interplay of LRRK2 with chaperone-mediated autophagy

Abstract: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease. We found LRRK2 to be degraded in lysosomes by chaperone-mediated autophagy (CMA), whereas the most common pathogenic mutant form of LRRK2, G2019S, was poorly degraded by this pathway. In contrast to the behavior of typical CMA substrates, lysosomal binding of both wild-type and several pathogenic mutant LRRK2 proteins was enhanced in the presence of other CMA substrates, which interfered with the organization of the CMA translocation complex, resulting in defective CMA. Cells responded to such LRRK2-mediated CMA compromise by increasing levels of the CMA lysosomal receptor, as seen in neuronal cultures and brains of LRRK2 transgenic mice, induced pluripotent stem cell-derived dopaminergic neurons and brains of Parkinson's disease patients with LRRK2 mutations. This newly described LRRK2 self-perpetuating inhibitory effect on CMA could underlie toxicity in Parkinson's disease by compromising the degradation of α-synuclein, another Parkinson's disease-related protein degraded by this pathway.

TGF-β Signaling Regulates Neuronal C1q Expression and Developmental Synaptic Refinement

Abstract: Immune molecules, including complement proteins C1q and C3, have emerged as critical mediators of synaptic refinement and plasticity. Complement localizes to synapses and refines the developing visual system through C3-dependent microglial phagocytosis of synapses. Retinal ganglion cells (RGCs) express C1q, the initiating protein of the classical complement cascade, during retinogeniculate refinement; however, the signals controlling C1q expression and function remain elusive. Previous work implicated an astrocyte-derived factor in regulating neuronal C1q expression. Here we identify retinal transforming growth factor (TGF)-β as a key regulator of neuronal C1q expression and synaptic pruning in the developing visual system. Mice lacking TGF-β receptor II (TGFβRII) in retinal neurons had reduced C1q expression in RGCs and reduced synaptic localization of complement, and phenocopied refinement defects observed in complement-deficient mice, including reduced eye-specific segregation and microglial engulfment of RGC inputs. These data implicate TGF-β in regulating neuronal C1q expression to initiate complement- and microglia-mediated synaptic pruning.

The cortical angiome: an interconnected vascular network with noncolumnar patterns of blood flow

Abstract: What is the nature of the vascular architecture in the cortex that allows the brain to meet the energy demands of neuronal computations? We used high-throughput histology to reconstruct the complete angioarchitecture and the positions of all neuronal somata of multiple cubic millimeter regions of vibrissa primary sensory cortex in mouse. Vascular networks were derived from the reconstruction. In contrast with the standard model of cortical columns that are tightly linked with the vascular network, graph-theoretical analyses revealed that the subsurface microvasculature formed interconnected loops with a topology that was invariant to the position and boundary of columns. Furthermore, the calculated patterns of blood flow in the networks were unrelated to location of columns. Rather, blood sourced by penetrating arterioles was effectively drained by the penetrating venules to limit lateral perfusion. This analysis provides the underpinning to understand functional imaging and the effect of penetrating vessels strokes on brain viability.

A subpopulation of nociceptors specifically linked to itch

Abstract: Dorsal root ganglion neurons respond to both painful and itchy stimuli, but whether itch-specific neurons exist was, up until now, unknown. Here the authors describe a group of MrgprA3-expressing neurons that innervate the superficial layers of the skin and selectively sense itch.

Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis

Abstract: Oligodendrocytes associate with axons to establish myelin and provide metabolic support to neurons. In the spinal cord of amyotrophic lateral sclerosis (ALS) mice, oligodendrocytes downregulate transporters that transfer glycolytic substrates to neurons and oligodendrocyte progenitors (NG2(+) cells) exhibit enhanced proliferation and differentiation, although the cause of these changes in oligodendroglia is unknown. We found extensive degeneration of gray matter oligodendrocytes in the spinal cord of SOD1 (G93A) ALS mice prior to disease onset. Although new oligodendrocytes were formed, they failed to mature, resulting in progressive demyelination. Oligodendrocyte dysfunction was also prevalent in human ALS, as gray matter demyelination and reactive changes in NG2(+) cells were observed in motor cortex and spinal cord of ALS patients. Selective removal of mutant SOD1 from oligodendroglia substantially delayed disease onset and prolonged survival in ALS mice, suggesting that ALS-linked genes enhance the vulnerability of motor neurons and accelerate disease by directly impairing the function of oligodendrocytes.

Fast modulation of visual perception by basal forebrain cholinergic neurons

Abstract: The basal forebrain provides the primary source of cholinergic input to the cortex, and it plays a crucial role in promoting wakefulness and arousal. However, whether rapid changes in basal forebrain neuron spiking in awake animals can dynamically influence sensory perception is unclear. Here we show that basal forebrain cholinergic neurons rapidly regulate cortical activity and visual perception in awake, behaving mice. Optogenetic activation of the cholinergic neurons or their V1 axon terminals improved performance of a visual discrimination task on a trial-by-trial basis. In V1, basal forebrain activation enhanced visual responses and desynchronized neuronal spiking, which could partly account for the behavioral improvement. Conversely, optogenetic basal forebrain inactivation decreased behavioral performance, synchronized cortical activity and impaired visual responses, indicating the importance of cholinergic activity in normal visual processing. These results underscore the causal role of basal forebrain cholinergic neurons in fast, bidirectional modulation of cortical processing and sensory perception.

CD33 Alzheimer’s disease locus: Altered monocyte function and amyloid biology

Abstract: In our functional dissection of the CD33 Alzheimer's disease susceptibility locus, we found that the rs3865444(C) risk allele was associated with greater cell surface expression of CD33 in the monocytes (t50 = 10.06, P(joint) = 1.3 × 10(-13)) of young and older individuals. It was also associated with diminished internalization of amyloid-β 42 peptide, accumulation of neuritic amyloid pathology and fibrillar amyloid on in vivo imaging, and increased numbers of activated human microglia.

Noninvasive brain stimulation: from physiology to network dynamics and back.

Abstract: Noninvasive brain stimulation techniques have been widely used for studying the physiology of the CNS, identifying the functional role of specific brain structures and, more recently, exploring large-scale network dynamics. Here we review key findings that contribute to our understanding of the mechanisms underlying the physiological and behavioral effects of these techniques. We highlight recent innovations using noninvasive stimulation to investigate global brain network dynamics and organization. New combinations of these techniques, in conjunction with neuroimaging, will further advance the utility of their application.

Closed-loop optogenetic control of thalamus as a tool for interrupting seizures after cortical injury.

Abstract: In this study, the authors report that a focal cortical injury can induce changes in the excitability of thalamocortical neurons that contributes to the maintenance of cortical seizures. In addition, silencing these neurons via a closed-loop optogenetic approach is sufficient to interrupt these seizures. Cerebrocortical injuries such as stroke are a major source of disability. Maladaptive consequences can result from post-injury local reorganization of cortical circuits. For example, epilepsy is a common sequela of cortical stroke, but the mechanisms responsible for seizures following cortical injuries remain unknown. In addition to local reorganization, long-range, extra-cortical connections might be critical for seizure maintenance. In rats, we found that the thalamus, a structure that is remote from, but connected to, the injured cortex, was required to maintain cortical seizures. Thalamocortical neurons connected to the injured epileptic cortex underwent changes in HCN channel expression and became hyperexcitable. Targeting these neurons with a closed-loop optogenetic strategy revealed that reducing their activity in real-time was sufficient to immediately interrupt electrographic and behavioral seizures. This approach is of therapeutic interest for intractable epilepsy, as it spares cortical function between seizures, in contrast with existing treatments, such as surgical lesioning or drugs.

Suppression of eIF2α kinases alleviates Alzheimer's disease–related plasticity and memory deficits

Abstract: Expression of long-lasting synaptic plasticity and long-term memory requires protein synthesis, which can be repressed by phosphorylation of eukaryotic initiation factor 2 α-subunit (eIF2α). Elevated phosphorylation of eIF2α has been observed in the brains of Alzheimer's disease patients and Alzheimer's disease model mice. Therefore, we tested whether suppressing eIF2α kinases could alleviate synaptic plasticity and memory deficits in Alzheimer's disease model mice. Genetic deletion of eIF2α kinase PERK prevented enhanced phosphorylation of eIF2α and deficits in protein synthesis, synaptic plasticity and spatial memory in mice that express familial Alzheimer's disease-related mutations in APP and PSEN1. Similarly, deletion of another eIF2α kinase, GCN2, prevented impairments of synaptic plasticity and defects in spatial memory exhibited by the Alzheimer's disease model mice. Our findings implicate aberrant eIF2α phosphorylation as a previously unidentified molecular mechanism underlying Alzheimer's disease-related synaptic pathophysioloy and memory dysfunction and suggest that PERK and GCN2 are potential therapeutic targets for treatment of individuals with Alzheimer's disease.

Direct recordings of grid-like neuronal activity in human spatial navigation

Abstract: Grid cells in the entorhinal cortex appear to represent spatial location via a triangular coordinate system. Such cells, which have been identified in rats, bats and monkeys, are believed to support a wide range of spatial behaviors. Recording neuronal activity from neurosurgical patients performing a virtual-navigation task, we identified cells exhibiting grid-like spiking patterns in the human brain, suggesting that humans and simpler animals rely on homologous spatial-coding schemes.