Hindbrain modules differentially transform activity of single collicular neurons to coordinate movements.

Seemingly simple behaviors such as swatting a mosquito or glancing at a signpost involve the precise coordination of multiple body parts. Neural control of coordinated movements is widely thought to entail transforming a desired overall displacement into displacements for each body part. Here we reveal a different logic implemented in the mouse gaze system.

Transcriptional profiling of mouse projection neurons with VECTORseq.

Existing techniques for transcriptional profiling of projection neurons could be applied to only one neuronal population per experiment. To increase throughput, we developed VECTORseq, which repurposes retrogradely infecting viruses to deliver multiplexable RNA barcodes, enabling projection anatomy to be read out in single-cell datasets. In this protocol, we describe the delivery of viral barcodes to mouse brain to label different projection neurons.

Superior colliculus drives stimulus-evoked directionally biased saccades and attempted head movements in head-fixed mice.

Animals investigate their environments by directing their gaze towards salient stimuli. In the prevailing view, mouse gaze shifts entail head rotations followed by brainstem-mediated eye movements, including saccades to reset the eyes. These 'recentering' saccades are attributed to head movement-related vestibular cues.

Virally encoded connectivity transgenic overlay RNA sequencing (VECTORseq) defines projection neurons involved in sensorimotor integration.

Behavior arises from concerted activity throughout the brain. Consequently, a major focus of modern neuroscience is defining the physiology and behavioral roles of projection neurons linking different brain areas. Single-cell RNA sequencing has facilitated these efforts by revealing molecular determinants of cellular physiology and markers that enable genetically targeted perturbations such as optogenetics, but existing methods for sequencing defined projection populations are low throughput, painstaking, and costly.

Author Correction: Structural insights into μ-opioid receptor activation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Soma-Targeted Imaging of Neural Circuits by Ribosome Tethering.

Neuroscience relies on techniques for imaging the structure and dynamics of neural circuits, but the cell bodies of individual neurons are often obscured by overlapping fluorescence from axons and dendrites in surrounding neuropil. Here, we describe two strategies for using the ribosome to restrict the expression of fluorescent proteins to the neuronal soma. We show first that a ribosome-tethered nanobody can be used to trap GFP in the cell body, thereby enabling direct visualization of previously undetectable GFP fluorescence.

Dopamine receptor cooperativity synergistically drives dyskinesia, motor behavior, and striatal GABA neurotransmission in hemiparkinsonian rats.

The striatum undergoes significant neuroplasticity both in Parkinson's Disease (PD) and following dopamine (DA) replacement therapy with l-DOPA. Unfortunately, these changes also contribute to the emergence of l-DOPA-induced dyskinesia (LID). While convergent strategies have demonstrated independent roles for DA D1 -receptors (D1R) and D2-receptors (D2R) in LID, DA receptor cooperativity, either by cellular or circuit mechanisms, has also been implicated in the dyskinetic brain.

Improvement in ADMET Prediction with Multitask Deep Featurization.

The absorption, distribution, metabolism, elimination, and toxicity (ADMET) properties of drug candidates are important for their efficacy and safety as therapeutics. Predicting ADMET properties has therefore been of great interest to the computational chemistry and medicinal chemistry communities in recent decades. Traditional cheminformatics approaches, using learners such as random forests and deep neural networks, leverage fingerprint feature representations of molecules.

Synthesis of spiro-2,6-dioxopiperazine and spiro-2,6-dioxopyrazine scaffolds using amino acids in a three-component reaction to generate potential Sigma-1 (σ) receptor selective ligands.

A library-friendly approach to generate new scaffolds is decisive for the development of molecular probes, drug like molecules and preclinical entities. Here, we present the design and synthesis of novel heterocycles with spiro-2,6-dioxopiperazine and spiro-2,6-pyrazine scaffolds through a three-component reaction using various amino acids, ketones, and isocyanides. Screening of select compounds over fifty CNS receptors including G-protein coupled receptors (GPCRs), ion channels, transporters, and enzymes through the NIMH psychoactive drug screening program indicated that a novel spiro-2,6-dioxopyrazine scaffold, UVM147, displays high binding affinity at sigma-1 (σ) receptor in the nanomolar range.

PotentialNet for Molecular Property Prediction.

The arc of drug discovery entails a multiparameter optimization problem spanning vast length scales. The key parameters range from solubility (angstroms) to protein-ligand binding (nanometers) to toxicity (meters). Through feature learning-instead of feature engineering-deep neural networks promise to outperform both traditional physics-based and knowledge-based machine learning models for predicting molecular properties pertinent to drug discovery.

MoleculeNet: a benchmark for molecular machine learning.

Molecular machine learning has been maturing rapidly over the last few years. Improved methods and the presence of larger datasets have enabled machine learning algorithms to make increasingly accurate predictions about molecular properties. However, algorithmic progress has been limited due to the lack of a standard benchmark to compare the efficacy of proposed methods; most new algorithms are benchmarked on different datasets making it challenging to gauge the quality of proposed methods.

Discovery of novel brain permeable and G protein-biased beta-1 adrenergic receptor partial agonists for the treatment of neurocognitive disorders.

The beta-1 adrenergic receptor (ADRB1) is a promising therapeutic target intrinsically involved in the cognitive deficits and pathological features associated with Alzheimer's disease (AD). Evidence indicates that ADRB1 plays an important role in regulating neuroinflammatory processes, and activation of ADRB1 may produce neuroprotective effects in neuroinflammatory diseases. Novel small molecule modulators of ADRB1, engineered to be highly brain permeable and functionally selective for the G protein with partial agonistic activity, could have tremendous value both as pharmacological tools and potential lead molecules for further preclinical development.

Structural insights into µ-opioid receptor activation.

Activation of the μ-opioid receptor (μOR) is responsible for the efficacy of the most effective analgesics. To shed light on the structural basis for μOR activation, here we report a 2.1 Å X-ray crystal structure of the murine μOR bound to the morphinan agonist BU72 and a G protein mimetic camelid antibody fragment.

Structural biology. Structural basis for chemokine recognition and activation of a viral G protein-coupled receptor.

Chemokines are small proteins that function as immune modulators through activation of chemokine G protein-coupled receptors (GPCRs). Several viruses also encode chemokines and chemokine receptors to subvert the host immune response. How protein ligands activate GPCRs remains unknown.

Orientation columns in the mouse superior colliculus.

More than twenty types of retinal ganglion cells conduct visual information from the eye to the rest of the brain. Each retinal ganglion cell type tessellates the retina in a regular mosaic, so that every point in visual space is processed for visual primitives such as contrast and motion. This information flows to two principal brain centres: the visual cortex and the superior colliculus.

Synthesis, pharmacokinetics, and biological use of lysine-modified single-walled carbon nanotubes.

We aimed to create a more robust and more accessible standard for amine-modifying single-walled carbon nanotubes (SWCNTs). A 1,3-cycloaddition was developed using an azomethine ylide, generated by reacting paraformaldehyde and a side-chain-Boc (tert-Butyloxycarbonyl)-protected, lysine-derived alpha-amino acid, H-Lys(Boc)-OH, with purified SWCNT or C60. This cycloaddition and its lysine adduct provides the benefits of dense, covalent modification, ease of purification, commercial availability of reagents, and pH-dependent solubility of the product.

Dialytic Separation of Bundled, Functionalized Carbon Nanotubes from Carbonaceous Impurities.

Separating functionalized single-wall carbon nanotubes (SWCNTs) from functionalized amorphous carbon is challenging, due to their polydispersity and similar physicochemical properties. We describe a single-step, dialytic separation method that takes advantage of the ability of heavily functionalized SWCNTs to bundle in a polar environment while maintaining their solubility. Experiments on functionalized SWCNTs were compared with functionalized, C fullerenes (buckyballs) to probe the general applicability of the method and further characterize the bundling process.

Carbon nanotubes as vaccine scaffolds.

Carbon nanotubes display characteristics that are potentially useful in their development as scaffolds for vaccine compositions. These features include stability in vivo, lack of intrinsic immunogenicity, low toxicity, and the ability to be appended with multiple copies of antigens. In addition, the particulate nature of carbon nanotubes and their unusual properties of rapid entry into antigen-presenting cells, such as dendritic cells, make them especially useful as carriers of antigens.

New technologies for imaging synaptic partners.

Understanding the brain will require unraveling its synaptic circuitry, but methods that can reliably identify connected neurons are often excruciatingly slow. Although light microscopy can provide much higher throughput, synapses are smaller than the diffraction limit and cannot readily be assigned to particular presynaptic and postsynaptic cells without specialized labeling methods. Here we review the ongoing development of techniques that allow direct imaging of neural networks by specifically marking connected cells or their synapses.

A hub-and-spoke circuit drives pheromone attraction and social behaviour in C. elegans.

Innate social behaviours emerge from neuronal circuits that interpret sensory information on the basis of an individual's own genotype, sex and experience. The regulated aggregation behaviour of the nematode Caenorhabditis elegans, a simple animal with only 302 neurons, is an attractive system to analyse these circuits. Wild social strains of C.

GFP Reconstitution Across Synaptic Partners (GRASP) defines cell contacts and synapses in living nervous systems.

The identification of synaptic partners is challenging in dense nerve bundles, where many processes occupy regions beneath the resolution of conventional light microscopy. To address this difficulty, we have developed GRASP, a system to label membrane contacts and synapses between two cells in living animals. Two complementary fragments of GFP are expressed on different cells, tethered to extracellular domains of transmembrane carrier proteins.

Global 'worming'.

A report on the 16th International Meeting, Los Angeles, USA, 27 June-1 July 2007.

Caenorhabditis elegans SID-2 is required for environmental RNA interference.

In plants and in the nematode Caenorhabditis elegans, an RNAi signal can trigger gene silencing in cells distant from the site where silencing is initiated. In plants, this signal is known to be a form of dsRNA, and the signal is most likely a form of dsRNA in C. elegans as well.

Analysis of mouse embryonic patterning and morphogenesis by forward genetics.

Many aspects of the genetic control of mammalian embryogenesis cannot be extrapolated from other animals. Taking a forward genetic approach, we have induced recessive mutations by treatment of mice with ethylnitrosourea and have identified 43 mutations that affect early morphogenesis and patterning, including 38 genes that have not been studied previously. The molecular lesions responsible for 14 mutations were identified, including mutations in nine genes that had not been characterized previously.

Suppression of autoimmune disease after vaccination with autoreactive T cells that express Qa-1 peptide complexes.

The ability of autoreactive T cells to provoke autoimmune disease is well documented. The finding that immunization with attenuated autoreactive T cells (T cell vaccination, or TCV) can induce T cell-dependent inhibition of autoimmune responses has opened the possibility that regulatory T cells may be harnessed to inhibit autoimmune disease. Progress in the clinical application of TCV, however, has been slow, in part because the underlying mechanism has remained clouded in uncertainty.