See-through brains clarify connections

A chemical treatment that turns whole organs transparent offers a big boost to the field of ‘connectomics’ — the push to map the brain’s fiendishly complicated wiring. Scientists could use the technique to view large networks of neurons with unprecedented ease and accuracy. The technology also opens up new research avenues for old brains that were saved from patients and healthy donors.

Helen Shen
Nature 496, 151 (11 April 2013) doi:10.1038/496151a

Kwanghun Chung, et al
Structural and molecular interrogation of intact biological systems
Nature (2013) doi:10.1038/nature12107

A 'Light Switch' in Brain Illuminates Neural Networks

 There are cells in your brain that recognize very specific places, and have that as one of their main jobs. These cells, called place cells, are found in an area behind your temple called the hippocampus. While these cells must be sent information from nearby cells to do their job, so far no one has been able to determine exactly what kind of nerve cells, or neurons, work with place cells to craft the code they create for each location. Neurons come in many different types with specialized functions. Some respond to edges and borders, others to specific locations, others act like a compass and react to which way you turn your head.
Science News Apr. 4, 2013 

Sheng-Jia Zhang*,†, Jing Ye*, Chenglin Miao, Albert Tsao, Ignas Cerniauskas, Debora Ledergerber, May-Britt Moser, Edvard I. Moser. Optogenetic Dissection of Entorhinal-Hippocampal Functional Connectivity. Science, 5 April 2013: Vol. 340 no. 6128 DOI: 10.1126/science.1232627

DNA and Quantum Dots: All That Glitters Is Not Gold

A team of researchers at the National Institute of Standards and Technology (NIST) has shown that by bringing gold nanoparticles close to the dots and using a DNA template to control the distances, the intensity of a quantum dot's fluorescence can be predictably increased or decreased. This breakthrough opens a potential path to using quantum dots as a component in better photodetectors, chemical sensors and nanoscale lasers.

Science Daily, Jan. 25, 2013

Seung Hyeon Ko, Kan Du, J. Alexander Liddle.

Quantum-Dot Fluorescence Lifetime Engineering with DNA Origami Constructs. 

Angewandte Chemie International Edition, 2013; 52 (4): 1193 DOI:10.1002/anie.201206253

The Cell That Isn't: New Technique Captures Division of Membrane-Less Cells

A new technique allows scientists to study cell division without a cell membrane. There are several advantages: it can be physically constrained and manipulated; one can access nuclei which is normally buried deep in an opaque embryo; the method ican be combined with a wide-range of fruit fly genetics techniques. The method has revealed that, surprisingly, confined space not enough to restrict spindle size.

Science Daily, Jan 18 2013

Ivo A Telley, Imre Gáspár, Anne Ephrussi, Thomas Surrey.

A single Drosophila embryo extract for the study of mitosis ex vivo. 

Nature Protocols, 2013; 8 (2): 310 DOI:10.1038/nprot.2013.003

Light Switch Inside Brain: Laser Controls Individual Nerve Cells in Mouse

Activating and deactivating individual nerve cells in the brain is something many neuroscientists wish they could do, as it would help them to better understand how the brain works.  Scientists in Freiburg and Basel, Switzerland, have developed an implant that is able to genetically modify specific nerve cells, control them with light stimuli, and measure their electrical activity all at the same time. This novel 3-in-1 tool paves the way for completely new experiments in neurobiology.

Science Daily, Jan 16 2013

A polymer-based neural microimplant for optogenetic applications: design and first in vivo study
Birthe Rubehn, et al.
Lab Chip, 2013, Advance Article
DOI: 10.1039/C2LC40874K, First published on the web 03 Jan 2013

Layer-specific excitatory circuits differentially control recurrent network dynamics in the neocortex

In the absence of external stimuli, the mammalian neocortex shows intrinsic network oscillations. These dynamics are characterized by translaminar assemblies of neurons whose activity synchronizes rhythmically in space and time. How different cortical layers influence the formation of these spontaneous cellular assemblies is poorly understood. The author found that excitatory neurons in supragranular and infragranular layers have distinct roles in the regulation of intrinsic low-frequency oscillations in mice in vivo. Optogenetic activation of infragranular neurons generated network activity that resembled spontaneous events, whereas photoinhibition of these same neurons substantially attenuated slow ongoing dynamics. In contrast, light activation and inhibition of supragranular cells had modest effects on spontaneous slow activity. This study represents, to the best of our knowledge, the first causal demonstration that excitatory circuits located in distinct cortical layers differentially control spontaneous low-frequency dynamics.

Riccardo Beltramo,  et al.
Nature Neuroscience (2013) doi:10.1038/nn.3306, Published online 13 January 2013

Feedback Inhibition Enables Theta-Nested Gamma Oscillations and Grid Firing Fields

Cortical circuits are thought to multiplex firing rate codes with temporal codes that rely on oscillatory network activity, but the circuit mechanisms that combine these coding schemes are unclear. The authors establish with optogenetic activation of layer II of the medial entorhinal cortex that theta frequency drive to this circuit is sufficient to generate nested gamma frequency oscillations in synaptic activity. These nested gamma oscillations closely resemble activity during spatial exploration, are generated by local feedback inhibition without recurrent excitation, and have clock-like features suitable as reference signals for multiplexing temporal codes within rate-coded grid firing fields. In network models deduced from our data, feedback inhibition supports coexistence of theta-nested gamma oscillations with attractor states that generate grid firing fields. These results indicate that grid cells communicate primarily via inhibitory interneurons. This circuit mechanism enables multiplexing of oscillation-based temporal codes with rate-coded attractor states.

Hugh Pastoll, et al.
Neuron, Volume 77, Issue 1, 141-154, 9 January 2013, 10.1016/j.neuron.2012.11.032

Cortico-cortical projections in mouse visual cortex are functionally target specific

Neurons in primary sensory cortex have diverse response properties, whereas higher cortical areas are specialized. Specific connectivity may be important for areal specialization, particularly in the mouse, where neighboring neurons are functionally diverse. To examine whether higher visual areas receive functionally specific input from primary visual cortex (V1), the author used two-photon calcium imaging to measure responses of axons from V1 arborizing in three areas with distinct spatial and temporal frequency preferences. they found that visual preferences of presynaptic boutons in each area were distinct and matched the average preferences of recipient neurons. This specificity could not be explained by organization within V1 and instead was due to both a greater density and greater response amplitude of functionally matched boutons. Projections from a single layer (layer 5) and from secondary visual cortex were also matched to their target areas. Thus, transmission of specific information to downstream targets may be a general feature of cortico-cortical communication.

Lindsey L Glickfeld, 

Nature Neuroscience (2013) doi:10.1038/nn.3300

Quantitative analysis of peptides and proteins in biomedicine by targeted mass spectrometry

Targeted mass spectrometry (MS) is becoming widely used in academia and in pharmaceutical and biotechnology industries for sensitive and quantitative detection of proteins, peptides and post-translational modifications. In Nature methods,  Gillette and Carr describe the increasing importance of targeted MS technologies in clinical proteomics and the potential key roles these techniques will have in bridging biomedical discovery and clinical implementation.
Michael A Gillette & Steven A Carr

Nature Methods 10, 28–34 (2013) doi:10.1038/nmeth.2309

All-in-one optogenetics

Scientists reverse engineer fluorescent proteins for light-mediated control.
Optogenetics is a young discipline that is coming on strong in fields such as neuroscience and protein signaling. It refers to the use of light-sensitive proteins to control cellular processes in living cells and organisms. Optogenetic tools can also be used to sense biological processes. Each of these applications has been performed with separate protein tools—until now.  Michael Lin, at Stanford University, and his colleagues have adapted a fluorescent protein (FP) to act as a light switch for controlling protein interactions, creating a protein tool that can both mediate biological function and report its own activity.

Nature Methods 10, 16 (2013) doi:10.1038/nmeth.2323

Xin Zhou et al.
Optical Control of Protein Activity by Fluorescent Protein Domains
Science 9 November 2012: Vol. 338 no. 6108 pp. 810-814 DOI: 10.1126/science.1226854

A subpopulation of nociceptors specifically linked to itch

A method for tagging single transcripts with two fluorescent markers can be used to study many aspects of gene expression, including intrinsic noise in transcription or polymerase dynamics at a single gene, report Singer and colleagues.
Lian Han et al.
Nature Neuroscience (2012) doi:10.1038/nn.3289

The retina as a window to the brain—from eye research to CNS disorders

The eye is an extension of the CNS in terms of its development and anatomy, and in terms of its dialogue with the immune system. Many neurodegenerative disorders of the brain and spinal cord have manifestations in the eye, which are often evident before the emergence of clinical neurological symptoms. London et al. highlight how investigation of the eye represents a noninvasive approach to the detection and diagnosis of neurodegenerative disorders, and discuss how eye research could provide a valuable model to study CNS disorders.

Anat London, Inbal Benhar & Michal Schwartz
Nature Reviews Neurology 9, 44-53 (January 2013) | doi:10.1038/nrneurol.2012.227

A prefrontal cortex–brainstem neuronal projection that controls response to behavioural challenge

The prefrontal cortex (PFC) is thought to participate in high-level control of the generation of behaviours (including the decision to execute actions); indeed, imaging and lesion studies in human beings have revealed that PFC dysfunction can lead to either impulsive states with increased tendency to initiate action, or to amotivational states characterized by symptoms such as reduced activity, hopelessness and depressed mood. Considering the opposite valence of these two phenotypes as well as the broad complexity of other tasks attributed to PFC, the authors sought to elucidate the PFC circuitry that favours effortful behavioural responses to challenging situations. Here they develop and use a quantitative method for the continuous assessment and control of active response to a behavioural challenge, synchronized with single-unit electrophysiology and optogenetics in freely moving rats. In recording from the medial PFC (mPFC), they observed that many neurons were not simply movement-related in their spike-firing patterns but instead were selectively modulated from moment to moment, according to the animal’s decision to act in a challenging situation. Surprisingly, they next found that direct activation of principal neurons in the mPFC had no detectable causal effect on this behavior. 

Melissa R. Warden,  et al.
Nature (2012) doi:10.1038/nature11617,  Published online 18 November 2012

Studying genomic processes at the single-molecule level: introducing the tools and applications

To understand genomic processes such as transcription, translation or splicing, we need to be able to study their spatial and temporal organization at the molecular level. Single-molecule approaches provide this opportunity, allowing researchers to monitor molecular conformations, interactions or diffusion quantitatively and in real time in purified systems and in the context of the living cell. This Review introduces the types of application of single-molecule approaches that can enhance our understanding of genome function.

David Dulin, et al.
Nature Reviews Genetics 14, 9-22 (January 2013) |doi:10.1038/nrg3316

Optimization of a GCaMP Calcium Indicator for Neural Activity Imaging

Genetically encoded calcium indicators (GECIs) are powerful tools for systems neuroscience. Recent efforts in protein engineering have significantly increased the performance of GECIs. The state-of-the art single-wavelength GECI, GCaMP3, has been deployed in a number of model organisms and can reliably detect three or more action potentials in short bursts in several systems in vivo.
Akerboom J et al.

J Neurosci. 2012 Oct 3;32(40):13819-40. doi: 10.1523/JNEUROSCI.2601-12.2012.

Tian L et al.
Imaging neural activity in worms, flies and mice with improved GCaMP calcium indicators.
Nat Methods. 2009 Dec;6(12):875-81. doi: 10.1038/nmeth.1398. Epub 2009 Nov 8.

Genetically encoded optical indicators for the analysis of neuronal circuits

In a departure from previous top-down or bottom-up strategies used to understand neuronal circuits, many forward-looking research programs now place the circuit itself at their centre. This has led to an emphasis on the dissection and elucidation of neuronal circuit elements and mechanisms, and on studies that ask how these circuits generate behavioural outputs. This movement towards circuit-centric strategies is progressing rapidly as a result of technological advances that combine genetic manipulation with light-based methods. The core tools of these new approaches are genetically encoded optical indicators and actuators that enable non-destructive interrogation and manipulation of neuronal circuits in behaving animals with cellular-level precision. This Review examines genetically encoded reporters of neuronal function and assesses their value for circuit-oriented neuroscientific investigations.

Thomas Knöpfel
Nature Reviews Neuroscience 13, 687-700 (October 2012) | doi:10.1038/nrn3293

In vivo genome editing using a high-efficiency TALEN system

Improvements in artificial transcription activator-like effector nucleases (TALENs) provide a powerful new approach for targeted zebrafish genome editing and functional genomic applications1–5. Using the Goldy TALEN modified scaffold and zebrafish delivery system, it was shown that this enhanced TALEN toolkit has a high efficiency in inducing locus-specific DNA breaks in somatic and germline tissues. 
Science 21 December 2012
Nature (2013) Sept 23