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1.  Restoring visual function to blind mice with a photoswitch that exploits electrophysiological remodeling of retinal ganglion cells 
Neuron  2014;81(4):800-813.
Retinitis pigmentosa (RP) and age-related macular degeneration (AMD) are blinding diseases caused by the degeneration of rods and cones, leaving the remainder of the visual system unable to respond to light. Here we report a chemical photoswitch named DENAQ that restores retinal responses to white light of intensity similar to ordinary daylight. A single intraocular injection of DENAQ photosensitizes the blind retina for days, restoring electrophysiological and behavioral responses with no toxicity. Experiments on mouse strains with functional, non-functional, or degenerated rods and cones show that DENAQ is effective only in retinas with degenerated photoreceptors. DENAQ confers light sensitivity on a hyperpolarization-activated inward current that is enhanced in degenerated retina, enabling optical control of retinal ganglion cell firing The acceptable light sensitivity, favorable spectral sensitivity, and selective targeting to diseased tissue make DENAQ a prime drug candidate for vision restoration in patients with end-stage RP and AMD.
PMCID: PMC3933823  PMID: 24559673
2.  Dopamine neurons control striatal cholinergic neurons via regionally heterogeneous dopamine and glutamate signaling 
Neuron  2014;81(4):901-912.
Midbrain dopamine neurons fire in bursts conveying salient information. Bursts are associated with pauses in tonic firing of striatal cholinergic interneurons. While the reciprocal balance of dopamine and acetylcholine in the striatum is well known, how dopamine neurons control cholinergic neurons has not been elucidated. Here we show that dopamine neurons make direct fast dopaminergic and glutamatergic connections with cholinergic interneurons, with regional heterogeneity. Dopamine neurons drive a burst-pause firing sequence in cholinergic interneurons in the medial shell of the nucleus accumbens, mixed actions in the accumbens core, and a pause in the dorsal striatum. This heterogeneity is due mainly to regional variation in dopamine-neuron glutamate cotransmission. A single dose of amphetamine attenuates dopamine neuron connections to cholinergic interneurons with dose-dependent regional specificity. Overall, the present data indicate that dopamine neurons control striatal circuit function via discrete, plastic connections with cholinergic interneurons.
PMCID: PMC3933825  PMID: 24559678
3.  Central terminal sensitization of TRPV1 by descending serotonergic facilitation modulates chronic pain 
Neuron  2014;81(4):873-887.
The peripheral terminals of primary nociceptive neurons play an essential role in pain detection mediated by membrane receptors like TRPV1, a molecular sensor of heat and capsaicin. However, the contribution of central terminal TRPV1 in the dorsal horn to chronic pain has not been investigated directly. Combining primary sensory neuron-specific GCaMP3 imaging with a trigeminal neuropathic pain model, we detected robust neuronal hyperactivity in injured and uninjured nerves in the skin, soma in trigeminal ganglion, and central terminals in the spinal trigeminal nucleus. Extensive TRPV1 hyperactivity was observed in central terminals innervating all dorsal horn laminae. The central terminal TRPV1 sensitization was maintained by descending serotonergic (5-HT) input from the brainstem. Central blockade of TRPV1 or 5-HT/5-HT3A receptors attenuated central terminal sensitization, excitatory primary afferent inputs, and mechanical hyperalgesia in the territories of injured and uninjured nerves. Our results reveal new central mechanisms facilitating central terminal sensitization underlying chronic pain.
PMCID: PMC3943838  PMID: 24462040
4.  Corticostriatal output gating during selection from working memory 
Neuron  2014;81(4):930-942.
Convergent evidence suggests that corticostriatal interactions act as a gate to select the input to working memory (WM). However, not all information in WM is relevant for behavior simultaneously. For this reason, a second “output gate” might advantageously govern which contents of WM influence behavior. Here, we test whether frontostriatal circuits previously implicated in input gating also support output gating during selection from WM. FMRI of a hierarchical rule task with dissociable input and output gating demands demonstrated greater lateral PFC recruitment and frontostriatal connectivity during output gating. Moreover, PFC and striatum correlated with distinct behavioral profiles. Whereas PFC recruitment correlated with the mean efficiency of selection from WM, striatal recruitment and frontostriatal interactions correlated with its reliability, as though such dynamics stochastically gate WM's output. These results support the output gating hypothesis and suggest that contextual representations in PFC influence striatum to select which information in WM drives responding.
PMCID: PMC3955887  PMID: 24559680
5.  ApoE and Aβ in Alzheimer’s disease: accidental encounters or partners? 
Neuron  2014;81(4):740-754.
Among the three human apolipoprotein E (apoE) isoforms, apoE4 increases the risk of Alzheimer’s disease (AD). While transporting cholesterol is a primary function, apoE also regulates amyloid-β (Aβ) metabolism, aggregation and deposition. Although earlier work suggests that different affinities of apoE isoforms to Aβ might account for their effects on Aβ clearance, recent studies indicate that apoE also competes with Aβ for cellular uptake through apoE receptors. Thus, several factors likely determine the variable effects apoE has on Aβ. In this review, we examine biochemical, structural, and functional studies and propose testable models that address the complex mechanisms underlying apoE-Aβ interaction and how apoE4 may increase AD risk and also serve as a target pathway for therapy.
PMCID: PMC3983361  PMID: 24559670
Alzheimer’s disease; apolipoprotein E; amyloid-β; aggregation; clearance; cholesterol; endocytosis; lysosome; degradation; LRP1; LDLR; HSPG
6.  A local glutamate-glutamine cycle sustains synaptic excitatory transmitter release 
Neuron  2014;81(4):888-900.
Biochemical studies suggest that excitatory neurons are metabolically coupled with astrocytes to generate glutamate for release. However, the extent to which glutamatergic neurotransmission depends on this process remains controversial, as direct electrophysiological evidence is lacking. The distance between cell bodies and axon terminals predicts that glutamine-glutamate cycle is synaptically localized. Hence we investigated isolated nerve terminals in brain slices by transecting hippocampal Schaffer collaterals and cortical Layer-I axons. Stimulating with alternating periods of high frequency (20Hz) and rest (0.2Hz), we identified an activity dependent reduction in synaptic efficacy that correlated with reduced glutamate release. This was enhanced by inhibition of astrocytic glutamine synthetase and reversed or prevented by exogenous glutamine. Importantly, this activity dependence was also revealed with an in vivo derived natural stimulus both at network and cellular levels. These data provide direct electrophysiological evidence that an astrocyte-dependent glutamate-glutamine cycle is required to maintain active neurotransmission at excitatory terminals.
PMCID: PMC4001919  PMID: 24559677
7.  Photoreceptor-derived Activin Promotes Dendritic Termination and Restricts the Receptive Fields of First-order Interneurons in Drosophila 
Neuron  2014;81(4):830-846.
How CNS neurons form appropriately sized dendritic fields to encounter their presynaptic partners is poorly understood. The Drosophila medulla is organized in layers and columns, and innervated by medulla neurons dendrites and photoreceptor axons. Here we show that three types of medulla projection (Tm) neurons extend their dendrites in stereotyped directions and to distinct layers within a single column for processing retinotopic information. In contrast, the Dm8 amacrine neurons form a wide dendritic field to receive ~16 R7 photoreceptor inputs. R7- and R8-derived Activin/TGF-β selectively restricts the dendritic fields of their respective postsynaptic partners, Dm8 and Tm20, to the size appropriate for their functions. Canonical Activin signaling promotes dendritic termination without affecting dendritic routing direction or layer. Tm20 neurons lacking Activin signaling expanded their dendritic fields and aberrantly synapsed with neighboring photoreceptors. We suggest that afferent-derived Activin regulates the dendritic field size of their postsynaptic partners to ensure appropriate synaptic partnership.
PMCID: PMC4004379  PMID: 24462039
8.  Good housekeeping 
Neuron  2014;81(4):715-717.
In this issue of Neuron, Tani et al. (2014) revisit a disputed issue where biochemical and physiological data have provided conflicting results. Using a novel stimulation protocol, the authors isolate the contribution of the glutamate-glutamine cycle to excitatory synaptic transmission.
PMCID: PMC4017765  PMID: 24559665
astrocyte; glutamate-glutamine cycle
9.  Gliotransmitters Travel in Time and Space 
Neuron  2014;81(4):728-739.
The identification of the presence of active signaling between astrocytes and neurons in a process termed gliotransmission has caused a paradigm shift in our thinking about brain function. However, we are still in the early days of the conceptualization of how astrocytes influence synapses, neurons, networks and ultimately behavior. In this review, our goal is to identify emerging principles governing gliotransmission and consider the specific properties of this process that endow the astrocyte with unique functions in brain signal integration. We develop and present hypotheses aimed at reconciling confounding reports and define open questions to provide a conceptual framework for future studies. We propose that astrocytes mainly signals through high affinity slowly-desensitizing receptors to modulate neurons and perform integration in spatio-temporal domains complementary to those of neurons.
PMCID: PMC4107238  PMID: 24559669
10.  Statistical wiring of thalamic receptive fields optimizes spatial sampling of the retinal image 
Neuron  2014;81(4):943-956.
It is widely assumed that mosaics of retinal ganglion cells establish the optimal representation of visual space. However, relay cells in the visual thalamus often receive convergent input from several retinal afferents and, in cat, outnumber ganglion cells. To explore how the thalamus transforms the retinal image, we built a model of the retinothalamic circuit using experimental data and simple wiring rules. The model shows how the thalamus might form a resampled map of visual space with the potential to facilitate detection of stimulus position in the presence of sensor noise. Bayesian decoding conducted with the model provides support for this scenario. Despite its benefits, however, resampling introduces image blur, thus impairing edge perception. Whole-cell recordings obtained in vivo suggest that this problem is mitigated by arrangements of excitation and inhibition within the receptive field that effectively boost contrast borders, much like strategies used in digital image processing.
PMCID: PMC4114508  PMID: 24559681
11.  A Hard-wired Glutamatergic Circuit Pools and Relays UV Signals to Mediate Spectral Preference in Drosophila 
Neuron  2014;81(3):603-615.
Many visual animals have innate preferences for particular wavelengths of light, which can be modified by learning. Drosophila’s preference for UV over visible light requires UV-sensing R7 photoreceptors and specific wide-field amacrine neurons, called Dm8. Here we identify three types of medulla projection neurons downstream of R7 and Dm8, and show that selectively inactivating one of them (Tm5c) abolishes UV preference. Using a modified GRASP method to probe synaptic connections at the single-cell level, we reveal that each Dm8 neuron forms multiple synaptic contacts with Tm5c in the center of Dm8’s dendritic field, but sparse connections in the periphery. By single-cell transcript profiling and RNAi-mediated knockdown, we determine that Tm5c uses the kainate receptor Clumsy to receive excitatory glutamate input from Dm8. We conclude that R7s->Dm8->Tm5c form a hard-wired glutamatergic circuit that mediates UV preference by pooling ~16 R7 signals for transfer to the lobula, a higher visual center.
PMCID: PMC3920195  PMID: 24507194
12.  Insulin/IGF1 Signaling Inhibits Age-Dependent Axon Regeneration 
Neuron  2014;81(3):561-573.
The ability of injured axons to regenerate declines with age yet the mechanisms that regulate axon regeneration in response to age are not known. Here we show that axon regeneration in aging C. elegans motor neurons is inhibited by the conserved insulin/IGF1 receptor DAF-2. DAF-2’s function in regeneration is mediated by intrinsic neuronal activity of the forkhead transcription factor DAF-16/FOXO. DAF-16 regulates regeneration independently of lifespan, indicating that neuronal aging is an intrinsic, neuron specific, and genetically regulated process. In addition, we found that daf-18/PTEN inhibits regeneration independently of age and FOXO signaling, via the TOR pathway. Finally, DLK-1, a conserved regulator of regeneration, is downregulated by insulin/IGF1 signaling, bound by DAF-16 in neurons, and is required for both DAF-16- and DAF-18-mediated regeneration. Together, our data establish that insulin signaling specifically inhibits regeneration in aging adult neurons, and that this mechanism is independent of PTEN and TOR.
PMCID: PMC3924874  PMID: 24440228
13.  Astrocyte-derived Endothelin-1 inhibits remyelination through Notch activation 
Neuron  2014;81(3):588-602.
Oligodendrocyte progenitor cells (OPCs) can repair demyelinated lesions by maturing into myelin-producing oligodendrocytes. However, the OPC potential to differentiate can be prevented by inhibitory signals present in the pathological lesion environment. Identification of these signals is essential to promote OPC differentiation and lesion repair. We identified an endogenous inhibitor of remyelination, Endothelin-1 (ET-1), which is highly expressed in reactive astrocytes of demyelinated lesions. Using both gain- and loss-of-function approaches, we demonstrate that ET-1 drastically reduces the rate of remyelination. We also discovered that ET-1 acts mechanistically by promoting Notch activation in OPCs during remyelination through induction of Jagged1 expression in reactive astrocytes. Pharmacological inhibition of ET-signaling prevented Notch activation in demyelinated lesions, and accelerated remyelination. These findings reveal that ET-1 is a negative regulator of OPC differentiation and remyelination, and is potentially a novel therapeutic target to promote lesion repair in demyelinated tissue.
PMCID: PMC3935216  PMID: 24507193
14.  Axonal transport of TDP-43 mRNA granules in neurons is impaired by ALS-causing mutations 
Neuron  2014;81(3):536-543.
The RNA binding protein TDP-43 regulates RNA metabolism at multiple levels, including transcription, RNA splicing, and mRNA stability. TDP-43 is a major component of the cytoplasmic inclusions characteristic of amyotrophic lateral sclerosis and some types of frontotemporal lobar degeneration. The importance of TDP-43 in disease is underscored by the fact that dominant missense mutations are sufficient to cause disease, although the role of TDP-43 in pathogenesis is unknown. Here we show that TDP-43 forms cytoplasmic mRNP granules that undergo bidirectional, microtubule-dependent transport in neurons in vitro and in vivo and facilitate delivery of target mRNA to distal neuronal compartments. TDP-43 mutations impair this mRNA transport function in vivo and in vitro, including in stem cell-derived motor neurons from ALS patients bearing any one of three different TDP-43 ALS-causing mutations. Thus, TDP43 mutations that cause ALS lead to partial loss of a novel cytoplasmic function of TDP-43.
PMCID: PMC3939050  PMID: 24507191
15.  Adaptation disrupts motion integration in the primate dorsal stream 
Neuron  2014;81(3):674-686.
Sensory systems adjust continuously to the environment. The effects of recent sensory experience—or adaptation—are typically assayed by recording in a relevant subcortical or cortical network. However, adaptation effects cannot be localized to a single, local network. Adjustments in one circuit or area will alter the input provided to others, with unclear consequences for computations implemented in the downstream circuit. Here we show that prolonged adaptation with drifting gratings, which alters responses in the early visual system, impedes the ability of area MT neurons to integrate motion signals in plaid stimuli. Perceptual experiments reveal a corresponding loss of plaid coherence. A simple computational model shows how the altered representation of motion signals in early cortex can derail integration in MT. Our results suggest that the effects of adaptation cascade through the visual system, derailing the downstream representation of distinct stimulus attributes.
PMCID: PMC3955163  PMID: 24507198
adaptation; pattern motion; MT; hierarchical networks; cascading adaptation
16.  TDP-43 in ALS: Stay on target… Almost there 
Neuron  2014;81(3):463-465.
ALS is associated with RNA processing impairments involving the RNA-binding protein TDP-43. Pioneering a novel RNA beacon to illuminate RNA trafficking in neurons, Alami et al. discover a novel cytoplasmic function for TDP-43, suggesting a new disease mechanism.
PMCID: PMC3962496  PMID: 24507183
17.  Macrophages gain a partner at the table: Epidermal cells digestperipheral dendritic debris in Drosophila 
Neuron  2014;81(3):465-467.
PMCID: PMC3963384  PMID: 24507184
18.  Neural computations underlying arbitration between model-based and model-free learning 
Neuron  2014;81(3):687-699.
There is accumulating neural evidence to support the existence of two distinct systems for guiding action-selection in the brain, a deliberative “model-based” and a reflexive “model-free” system. However, little is known about how the brain determines which of these systems controls behavior at one moment in time. We provide evidence for an arbitration mechanism that allocates the degree of control over behavior by model-based and model-free systems as a function of the reliability of their respective predictions. We show that inferior lateral prefrontal and frontopolar cortex encode both reliability signals and the output of a comparison between those signals, implicating these regions in the arbitration process. Moreover, connectivity between these regions and model-free valuation areas is negatively modulated by the degree of model-based control in the arbitrator, suggesting that arbitration may work through modulation of the model-free valuation system when the arbitrator deems that the model-based system should drive behavior.
PMCID: PMC3968946  PMID: 24507199
19.  Cross-modal induction of thalamocortical potentiation leads to enhanced information processing in the auditory cortex 
Neuron  2014;81(3):664-673.
Sensory systems do not work in isolation; instead they show interactions that are specifically uncovered during sensory loss. To identify and characterize these interactions, we investigated whether visual deprivation leads to functional enhancement in primary auditory cortex (A1). We compared sound-evoked responses of A1 neurons in visually-deprived animals to those from normally-reared animals. Here we show that visual deprivation leads to improved frequency selectivity as well as increased frequency and intensity discrimination performance of A1 neurons. Furthermore, we demonstrate in vitro that in adults, visual deprivation strengthens thalamocortical (TC-) synapses in A1, but not in primary visual cortex (V1). Because deafening potentiated TC-synapses in V1 but not A1, cross-modal TC-potentiation seems to be a general property of adult cortex. Our results suggest that adults retain the capability for cross-modal changes while such capability is absent within a sensory modality. Thus multimodal training paradigms might be beneficial in sensory processing disorders.
PMCID: PMC4023256  PMID: 24507197
20.  SIRT1 in neurodevelopment and brain senescence 
Neuron  2014;81(3):471-483.
Sirtuins are nicotinamide adenine dinucleotide (NAD+)-dependent deacylases that have traditionally been linked with calorie restriction and aging in mammals. These proteins also play an important role in maintaining neuronal health during aging. During neuronal development, the SIR2 ortholog SIRT1 is structurally important, promoting axonal elongation, neurite outgrowth and dendritic branching. This sirtuin also plays a role in memory formation by modulating synaptic plasticity. Hypothalamic functions that affect feeding behavior, endocrine function and circadian rhythmicity are all regulated by SIRT1. Finally, SIRT1 plays protective roles in several neurodegenerative diseases including Alzheimer’s, Parkinson’s and motor neuron diseases, which may relate to its functions in metabolism, stress resistance and genomic stability. Drugs that activate SIRT1 may offer a promising approach to treat these disorders.
PMCID: PMC4040287  PMID: 24507186
sirtuin; histone deacetylase; aging; cognitive function; neurodevelopment; neurodegeneration; Alzheimer’s disease; Parkinson’s disease; Huntington’s disease; motor neuron disease; multiple sclerosis
21.  Neural Population Tuning Links Visual Cortical Anatomy to Human Visual Perception 
Neuron  2015;85(3):641-656.
The anatomy of cerebral cortex is characterized by two genetically independent variables, cortical thickness and cortical surface area, that jointly determine cortical volume. It remains unclear how cortical anatomy might influence neural response properties and whether such influences would have behavioral consequences. Here, we report that thickness and surface area of human early visual cortices exert opposite influences on neural population tuning with behavioral consequences for perceptual acuity. We found that visual cortical thickness correlated negatively with the sharpness of neural population tuning and the accuracy of perceptual discrimination at different visual field positions. In contrast, visual cortical surface area correlated positively with neural population tuning sharpness and perceptual discrimination accuracy. Our findings reveal a central role for neural population tuning in linking visual cortical anatomy to visual perception and suggest that a perceptually advantageous visual cortex is a thinned one with an enlarged surface area.
•Variability in cortical thickness and surface area has opposite functional impacts•Smaller human visual cortical thickness links to high neural and perceptual acuity•Larger human visual cortical surface area links to high neural and perceptual acuity
Song et al. showed that large brains are not necessarily advantageous. Instead, the two dimensions, thickness and surface area, of human brain have opposite impacts on visual perception. A perceptually advantageous brain is a thinned one with enlarged surface area.
PMCID: PMC4321887  PMID: 25619658
22.  Optogenetic Inactivation Modifies Monkey Visuomotor Behavior 
Neuron  2012;76(5):901-907.
A critical technique for understanding how neuronal activity contributes to behavior is determining whether perturbing it changes behavior. The advent of optogenetic techniques allows the immediately reversible alteration of neuronal activity in contrast to chemical approaches lasting minutes to hours. Modification of behavior using optogenetics has had substantial success in rodents, but has not been as successful in monkeys. Here we show how optogenetic inactivation of superior colliculus neurons in awake monkeys leads to clear and repeatable behavioral deficits in the metrics of saccadic eye movements. We used our observations to evaluate principles governing the use of optogenetic techniques in the study of the neuronal bases of behavior in monkeys, particularly how experimental design must address relevant parameters, such as the application of light to subcortical structures, the spread of viral injections, and the extent of neuronal inactivation with light.
PMCID: PMC4311889  PMID: 23217739
optogenetics; inactivation; ArchT; saccades; superior colliculus
23.  Chemogenetic synaptic silencing of neural circuits localizes a hypothalamus→midbrain pathway for feeding behavior 
Neuron  2014;82(4):797-808.
Brain function is mediated by neural circuit connectivity, and elucidating the role of connections is aided by techniques to block their output. We developed cell type-selective, reversible synaptic inhibition tools for mammalian neural circuits by leveraging G-protein signaling pathways to suppress synaptic vesicle release. Here, we find that the pharmacologically selective designer Gi-protein coupled receptor, hM4D, is a presynaptic silencer in the presence of its cognate ligand clozapine-N-oxide (CNO). Activation of hM4D signaling sharply reduced synaptic release probability and synaptic current amplitude. To demonstrate the utility of this tool for neural circuit perturbations, we developed an axon-selective hM4D–neurexin variant and used spatially targeted intracranial CNO injections to localize circuit connections from the hypothalamus to the midbrain responsible for feeding behavior. This synaptic silencing approach is broadly applicable for cell type-specific and axon projection-selective functional analysis of diverse neural circuits.
PMCID: PMC4306349  PMID: 24768300
24.  Hypothalamic Survival Circuits: Blueprints for Purposive Behaviors 
Neuron  2013;77(5):810-824.
Neural processes that direct an animal’s actions toward environmental goals are critical elements for understanding behavior. The hypothalamus is closely associated with motivated behaviors required for survival and reproduction. Intense feeding, drinking, aggressive, and sexual behaviors can be produced by a simple neuronal stimulus applied to discrete hypothalamic regions. What can these “evoked behaviors” teach us about the neural processes that determine behavioral intent and intensity? Small populations of neurons sufficient to evoke a complex motivated behavior may be used as entry points to identify circuits that energize and direct behavior to specific goals. Here, I review recent applications of molecular genetic, optogenetic, and pharmacogenetic approaches that overcome previous limitations for analyzing anatomically complex hypothalamic circuits and their interactions with the rest of the brain. These new tools have the potential to bridge the gaps between neurobiological and psychological thinking about the mechanisms of complex motivated behavior.
PMCID: PMC4306350  PMID: 23473313
25.  [No title available] 
PMCID: PMC3904133  PMID: 24462102

Results 1-25 (1848)