One Form of Neuron Turned Into Another in Brain

 A new finding by Harvard stem cell biologists turns one of the basics of neurobiology on its head -- demonstrating that it is possible to turn one type of already differentiated neuron into another within the brain. The discovery by Paola Arlotta and Caroline Rouaux "tells you that maybe the brain is not as immutable as we always thought, because at least during an early window of time one can reprogram the identity of one neuronal class into another," said Arlotta.

Science Daily, Jan. 20, 2013

Caroline Rouaux, Paola Arlotta.

Direct lineage reprogramming of post-mitotic callosal neurons into corticofugal neurons in vivo. 

Nature Cell Biology, 2013; DOI: 10.1038/ncb2660

Human brain evolution: transcripts, metabolites and their regulators

What evolutionary events led to the emergence of human cognition? Although the genetic differences separating modern humans from both non-human primates (for example, chimpanzees) and archaic hominins (Neanderthals and Denisovans) are known, linking human-specific mutations to the cognitive phenotype remains a challenge.  The new strategy is to focus on human-specific changes at the level of intermediate phenotypes, such as gene expression and metabolism, in conjunction with evolutionary changes in gene regulation involving transcription factors, microRNA and proximal regulatory elements. In this Review the authors show how this strategy has yielded some of the first hints about the mechanisms of human cognition.

Mehmet Somel, et al.
Nature Reviews Neuroscience 14, 112-127 (February 2013) | doi:10.1038/nrn3372

Discrete genetic modules are responsible for complex burrow evolution in Peromyscus mice

The genetics of behavioural differences between closely related species are less well understood than the genetics of morphological differences. Many animals build elaborate structures — such as hives, nests and burrows — that 'evolve' as natural selection acts on the behaviour of their builders. This study uses an example of this phenomenon to tackle the question of whether complex behaviours evolve through one or few genetic changes that each influence many aspects of behaviour, or by accumulation of several genetic changes that generate behavioural complexity only when combined. Hopi Hoekstra and colleagues show that the complex burrows created by oldfield mice are governed by several genetic modules, each controlling an aspect of burrow size or shape. This modularity in burrow architecture suggests that complex behaviour may result from the combination of genetically determined behaviours that have accumulated over time.

Jesse N. Weber, et al.

Nature 493, 402–405 (17 January 2013) doi:10.1038/nature11816

New Implant Replaces Impaired Middle Ear

Functionally deaf patients can gain normal hearing with a new implant that replaces the middle ear. The unique invention from the Chalmers University of Technology has been approved for a clinical study. The first operation was performed on a patient in December 2012.

Jan. 14, 2013 — Science Daily

Regenerate Sensory Hair Cells, Restore Hearing to Noise-Damaged Ears

Hearing loss is a significant public health problem affecting almost 50 million people in the United States alone. Sensorineural hearing loss is the most common form and is caused by the loss of sensory hair cells in the cochlea. Hair cell loss results from a variety of factors including noise exposure, aging, toxins, infections, and certain antibiotics and anti-cancer drugs. Although hearing aids and cochlear implants can ameliorate the symptoms somewhat, there are no known treatments to restore hearing, because auditory hair cells in mammals, unlike those in birds or fish, do not regenerate once lost. Auditory hair cell replacement holds great promise as a treatment that could restore hearing after loss of hair cells.

In the Jan. 10 issue of Neuron, Massachusetts Eye and Ear and Harvard Medical School researchers demonstrate for the first time that hair cells can be regenerated in an adult mammalian ear by using a drug to stimulate resident cells to become new hair cells, resulting in partial recovery of hearing in mouse ears damaged by noise trauma. This finding holds great potential for future therapeutic application that may someday reverse deafness in humans.

Notch Inhibition Induces Cochlear Hair Cell Regeneration and Recovery of Hearing after Acoustic Trauma
Kunio Mizutari, et al.
Neuron, Volume 77, Issue 1, 58-69, 9 January 2013, 10.1016/j.neuron.2012.11.032

Microglia: New Roles for the Synaptic Stripper

Any pathologic event in the brain leads to the activation of microglia, the immunocompetent cells of the central nervous system. In recent decades diverse molecular pathways have been identified by which microglial activation is controlled and by which the activated microglia affects neurons. In the normal brain microglia were considered “resting,” but it has recently become evident that they constantly scan the brain environment and contact synapses. Activated microglia can remove damaged cells as well as dysfunctional synapses, a process termed “synaptic stripping.” Here the author summarize evidence that molecular pathways characterized in pathology are also utilized by microglia in the normal and developing brain to influence synaptic development and connectivity, and therefore should become targets of future research. Microglial dysfunction results in behavioral deficits, indicating that microglia are essential for proper brain function. This defines a new role for microglia beyond being a mere pathologic sensor.

Neuron, Volume 77, Issue 1, 10-18, 9 January 2013, 10.1016/j.neuron.2012.12.023

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

Shaping Our Minds: Stem and Progenitor Cell Diversity in the Mammalian Neocortex

The neural circuits of the mammalian neocortex are crucial for perception, complex thought, cognition, and consciousness. This circuitry is assembled from many different neuronal subtypes with divergent properties and functions. Here, we review recent studies that have begun to clarify the mechanisms of cell-type specification in the neocortex, focusing on the lineage relationships between neocortical progenitors and subclasses of excitatory projection neurons. These studies reveal an unanticipated diversity in the progenitor pool that requires a revised view of prevailing models of cell-type specification in the neocortex. We propose a “sequential progenitor-diversification model” that integrates current knowledge to explain how projection neuron diversity is achieved by mechanisms acting on proliferating progenitors and their postmitotic offspring. We discuss the implications of this model for our understanding of brain evolution and pathological states of the neocortex.

Neuron, Volume 77, Issue 1, 19-34, 9 January 2013, 10.1016/j.neuron.2012.12.022

Ion Channels | TRP Channels in Drosophila Auditory Transduction

In this study, Lehnert et al. record spikes and subthreshold activity from a genetically defined population ofDrosophila auditory receptor neurons. These recordings reveal that several TRP family members play distinct roles in converting movement to transduction currents.

Lehnert et al.
Neuron, Volume 77, Issue 1, 115-128, 9 January 2013
10.1016/j.neuron.2012.11.030

Eliminating Useless Information Important to Learning, Making New Memories

As we age, it just may be the ability to filter and eliminate old information -- rather than take in the new stuff -- that makes it harder to learn, scientists report.  "When you are young, your brain is able to strengthen certain connections and weaken certain connections to make new memories," said Dr. Joe Z. Tsien, neuroscientist at Georgia Regents University.  It's that critical weakening that appears hampered in the older brain, according to a study in the journalScientific Reports.

The NMDA receptor in the brain's hippocampus is like a switch for regulating learning and memory, working through subunits called NR2A and NR2B. NR2B is expressed in higher percentages in children, enabling neurons to talk a fraction of a second longer; make stronger bonds, called synapses; and optimize learning and memory. This formation of strong bonds is called long-term potentiation. The ratio shifts after puberty, so there is more NR2A and slightly reduced communication time between neurons.  When Tsien and his colleagues genetically modified mice that mimic the adult ratio -- more NR2A, less NR2B -- they were surprised to find the rodents were still good at making strong connections and short-term memories but had an impaired ability to weaken existing connections, called long-term depression, and to make new long-term memories as a result. It's called information sculpting and adult ratios of NMDA receptor subunits don't appear to be very good at it.

Science Daily, Jan 9, 2012 
Zhenzhong Cui, et al
Scientific Reports 3, Article number: 1036 doi:10.1038/srep01036

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

In vivo reprogramming of circuit connectivity in postmitotic neocortical neurons

The molecular mechanisms that control how progenitors generate distinct subtypes of neurons, and how undifferentiated neurons acquire their specific identity during corticogenesis, are increasingly understood. However, whether postmitotic neurons can change their identity at late stages of differentiation remains unknown. To study this question, the authors developed an electrochemical in vivo gene delivery method to rapidly manipulate gene expression specifically in postmitotic neurons. Using this approach, they found that the molecular identity, morphology, physiology and functional input-output connectivity of layer 4 mouse spiny neurons could be specifically reprogrammed during the first postnatal week by ectopic expression of the layer 5B output neuron–specific transcription factor Fezf2. These findings reveal a high degree of plasticity in the identity of postmitotic neocortical neurons and provide a proof of principle for postnatal re-engineering of specific neural microcircuits in vivo.
Andres De la Rossa, et al.
Nature Neuroscience (2013) doi:10.1038/nn.3299

Dual origins of the mammalian accessory olfactory bulb revealed by an evolutionarily conserved migratory stream

The accessory olfactory bulb (AOB) is a critical olfactory structure that has been implicated in mediating social behavior. It receives input from the vomeronasal organ and projects to targets in the amygdaloid complex. Its anterior and posterior components (aAOB and pAOB) display molecular, connectional and functional segregation in processing reproductive and defensive and aggressive behaviors, respectively. We observed a dichotomy in the development of the projection neurons of the aAOB and pAOB in mice. We found that they had distinct sites of origin and that different regulatory molecules were required for their specification and migration. aAOB neurons arose locally in the rostral telencephalon, similar to main olfactory bulb neurons. In contrast, pAOB neurons arose caudally, from the neuroepithelium of the diencephalic-telencephalic boundary, from which they migrated rostrally to reach their destination. This unusual origin and migration is conserved in Xenopus, providing an insight into the origin of a key component of this system in evolution.

Dhananjay Huilgol, et al.
Nature Neuroscience (2013) doi:10.1038/nn.3297

New Information on Autism and Genetics

Research out of the George Washington University reveals another piece of the puzzle in a genetic developmental disorder that causes behavioral diseases such as autism.
"It tell us that in very early development, those with 22q11.2 deletion syndrome do not make enough cells in one case, and do not put the other cells in the right place. This occurs not because of some degenerative change, but because the mechanisms that make these cells and put them in the right place during the first step of development have gone awry due to mutation,"said LaMantia.

Science Daily - Jan. 3, 2013
T. M. Maynard, et.al.
A comprehensive analysis of 22q11 gene expression in the developing and adult brain. 

Proceedings of the National Academy of Sciences, 2003; 100 (24): 14433 DOI:10.1073/pnas.2235651100

The Immune System's Compact Genomic Counterpart

Much of the human genome derives from self-serving DNA strands known as transposons. These genetic gypsies often jump to new chromosome locations, sometimes disabling genes and even triggering cancer. For that reason, a specialized group of RNA molecules known as piRNAs are the superheroes of animal genomes. piRNAs team up with certain proteins to shackle transposons in animal germline cells, creating a molecular defense that scientists liken to an immune system for the genome.
Science 4 January 2013: vol. 339 no. 6115 25-27

Your Brain On Big Bird: Sesame Street Helps to Reveal Patterns of Neural Development

Using brain scans of children and adults watching Sesame Street, cognitive scientists are learning how children's brains change as they develop intellectual abilities like reading and math,
Scientists are just beginning to use brain imaging to understand how humans process thought during real-life experiences. For example, researchers have compared scans of adults watching an entertaining movie to see if neural responses are similar across different individuals. "But this is the first study to use the method as a tool for understanding development," says lead author Jessica Cantlon, an assistant professor in brain and cognitive sciences at the University of Rochester.

Science Daily, Jan 3, 2012

Cantlon JF, Li R.

Neural Activity during Natural Viewing of Sesame Street Statistically Predicts Test Scores in Early Childhood. 

PLoS Biol, 2013; 11(1): e1001462 DOI:10.1371/journal.pbio.1001462

2012: Signaling Breakthroughs of the Year

With input from the members of the Board of Reviewing Editors and editorial staff, Science Signaling puts the spotlight on the hottest signaling research of 2012. The connection between signaling and metabolism continues to be an important area. Signaling breakthroughs in cancer, immunology, developmental biology, neuroscience, and microbiology all made the list. Structural and molecular insights into signaling proteins and networks are also beginning to not only yield potential therapeutic targets but also lead to successful efforts between synthetic biologists and clinicians in the treatment of cancer.

Sci. Signal., 1 January 2013 Vol. 6, Issue 256, p. eg1 [DOI: 10.1126/scisignal.2003881]

The NaV1.7 sodium channel: from molecule to man

The voltage-gated sodium channel NaV1.7 is preferentially expressed in peripheral somatic and visceral sensory neurons, olfactory sensory neurons and sympathetic ganglion neurons. NaV1.7 accumulates at nerve fibre endings and amplifies small subthreshold depolarizations, poising it to act as a threshold channel that regulates excitability. Genetic and functional studies have added to the evidence that NaV1.7 is a major contributor to pain signalling in humans, and homology modelling based on crystal structures of ion channels suggests an atomic-level structural basis for the altered gating of mutant NaV1.7 that causes pain.

Sulayman D. Dib-Hajj, et al.

Nature Reviews Neuroscience 14, 49-62 (January 2013) | doi:10.1038/nrn3404

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