Epigenetic mechanisms in the development and maintenance of dopaminergic neurons

Mesodiencephalic dopaminergic (mdDA) neurons are located in the ventral mesodiencephalon and are involved in psychiatric disorders and severely affected in neurodegenerative diseases such as Parkinson’s disease. mdDA neuronal development has received much attention in the last 15 years and many transcription factors involved in mdDA specification have been discovered. More recently however, the impact of epigenetic regulation has come into focus, and it’s emerging that the processes of histone modification and DNA methylation form the basis of genetic switches that operate during mdDA development. Here, we review the epigenetic control of mdDA development, maturation and maintenance. As we highlight, epigenetic mechanisms play a pivotal role in all of these processes and the knowledge gathered from studying epigenetics in these contexts may aid our understanding of mdDA-related pathologies.

Hendrikus J. van Heesbeen, et al
Development140, 1159-1169.   March 15, 2013
doi:10.1242/dev.089359  

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

Why Wolves Are Forever Wild, but Dogs Can Be Tamed

Dogs and wolves are genetically so similar, it's been difficult for biologists to understand why wolves remain fiercely wild, while dogs can gladly become "man's best friend." Now, doctoral research by evolutionary biologist Kathryn Lord at the University of Massachusetts Amherst suggests the different behaviors are related to the animals' earliest sensory experiences and the critical period of socialization. Details appear in the current issue of Ethology.

When the socialization window is open, wolf and dog pups begin walking and exploring without fear and will retain familiarity throughout their lives with those things they contact. Domestic dogs can be introduced to humans, horses and even cats at this stage and be comfortable with them forever. But as the period progresses, fear increases and after the window closes, new sights, sounds and smells will elicit a fear response.  Through observations, Lord confirmed that both wolf pups and dogs develop the sense of smell at age two weeks, hearing at four weeks and vision by age six weeks on average. However, these two subspecies enter the critical period of socialization at different ages. Dogs begin the period at four weeks, while wolves begin at two weeks. Therefore, how each subspecies experiences the world during that all-important month is extremely different, and likely leads to different developmental paths, she says.
Science Daily, Jan. 17, 2013

Kathryn Lord.

A Comparison of the Sensory Development of Wolves (Canis lupus lupus) and Dogs (Canis lupus familiaris). 

Ethology, 2013; 119 (2): 110 DOI:10.1111/eth.12044

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

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

'Junk DNA' Made Visible Before the Final Cut

Research findings from the University of North Carolina School of Medicine are shining a light on an important regulatory role performed by the so-called dark matter, or "junk DNA," within each of our genes. The new study reveals snippets of information contained in dark matter that can alter the way a gene is assembled. "These small sequences of genetic information tell the gene how to splice, either by enhancing the splicing process or inhibiting it. The research opens the door for studying the dark matter of genes. And it helps us further understand how mutations or polymorphisms affect the functions of any gene," said study senior author, Zefeng Wang, PhD, assistant professor of pharmacology in the UNC School of Medicine and a member of UNC Lineberger Comprehensive Cancer Center.Science Daily - Jan. 7, 2013
Yang Wang, et al.
A complex network of factors with overlapping affinities represses splicing through intronic elements.
Nature Structural & Molecular Biology, 2012; 20 (1): 36 DOI: 10.1038/nsmb.2459

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

A cellular mechanism for cortical associations: an organizing principle for the cerebral cortex

A basic feature of intelligent systems such as the cerebral cortex is the ability to freely associate aspects of perceived experience with an internal representation of the world and make predictions about the future. Here, a hypothesis is presented that the extraordinary performance of the cortex derives from an associative mechanism built in at the cellular level to the basic cortical neuronal unit: the pyramidal cell. The mechanism is robustly triggered by coincident input to opposite poles of the neuron, is exquisitely matched to the large- and fine-scale architecture of the cortex, and is tightly controlled by local microcircuits of inhibitory neurons targeting subcellular compartments. This article explores the experimental evidence and the implications for how the cortex operates.

Matthew Larkum
Trends in Neurosciences, 26 December 2012
10.1016/j.tins.2012.11.006

Whole-Genome Sequencing in Autism Identifies Hot Spots for De Novo Germline Mutation

An international team, led by researchers from UC San Diego,  has discovered that "random" mutations in the genome are not quite so random after all. Their study, to be published in the journal Cell on December 21, shows that the DNA sequence in some regions of the human genome is quite volatile and can mutate ten times more frequently than the rest of the genome. Genes that are linked to autism and a variety of other disorders have a particularly strong tendency to mutate.
Science Daily, Dec 20, 2012
Jacob J. Michaelson et al.
Cell, Volume 151, Issue 7, 1431-1442, 21 December 2012

The ventral visual pathway: an expanded neural framework for the processing of object quality

Since the original characterization of the ventral visual pathway, our knowledge of its neuroanatomy, functional properties, and extrinsic targets has grown considerably. Here the authors synthesize this recent evidence and propose that the ventral pathway is best understood as a recurrent occipitotemporal network containing neural representations of object quality both utilized and constrained by at least six distinct cortical and subcortical systems. Each system serves its own specialized behavioral, cognitive, or affective function, collectively providing the raison d’être for the ventral visual pathway. This expanded framework contrasts with the depiction of the ventral visual pathway as a largely serial staged hierarchy culminating in singular object representations and more parsimoniously incorporates attentional, contextual, and feedback effects.

Dwight J. Kravitz, et al.

Trends in Cognitive Sciences, Volume 17, Issue 1, 26-49, 21 December 2012
10.1016/j.tics.2012.10.011

Retooling spare parts: gene duplication and cognition

Two new studies provide experimental evidence of how ancient genomic duplications of synaptic genes provided the substrate for diversification that ultimately expanded vertebrate cognitive complexity.

T Grant Belgard & Daniel H Geschwind
Nature Neuroscience 16, 6–8 (2013) doi:10.1038/nn.3292

Published online 21 December 2012

Origin of Life: Hypothesis Traces First Protocells Back to Emergence of Cell Membrane Bioenergetics

A coherent pathway -- which starts from no more than rocks, water and carbon dioxide and leads to the emergence of the strange bio-energetic properties of living cells -- has been traced for the first time in a major hypothesis paper in Cell this week.
Science Daily on Dec. 20, 2012
Reference : Nick Lane, William F. Martin. The Origin of Membrane Bioenergetics.
Cell, 2012; 151 (7): 1406

Woman With Quadriplegia Feeds Herself Chocolate Using Mind-Controlled Robot Arm

Reaching out to high five someone, grasping and moving objects of different shapes and sizes, feeding herself dark chocolate. For Jan Scheuermann and a team of researchers from the University of Pittsburgh School of Medicine and UPMC, accomplishing these seemingly ordinary tasks demonstrated for the first time that a person with longstanding quadriplegia can maneuver a mind-controlled, human-like robot arm in seven dimensions (7D) to consistently perform many of the natural and complex motions of everyday life.
UPMC/University of Pittsburgh Schools of the Health Sciences, News release on Dec 16, 2012

CBS 60 Minutes, Dec 30, 2012

Evolution of GluN2A/B cytoplasmic domains diversified vertebrate synaptic plasticity and behavior

Understanding the mechanisms underlying the many forms of vertebrate behavior is a central objective of neuroscience and, although studied extensively at the cellular and circuit levels, very little is known about the underlying molecular evolutionary events. How did genome evolution give rise to the many forms of learning, emotional behavior and motor functions and generate the subtlety of synaptic regulation that is manifest in the mammalian brain?

Two genome duplications early in the vertebrate lineage expanded gene families, including GluN2 subunits of the NMDA receptor. Diversification between the four mammalian GluN2 proteins occurred primarily at their intracellular C-terminal domains (CTDs). To identify shared ancestral functions and diversified subunit-specific functions, the authors exchanged the exons encoding the GluN2A (also known as Grin2a) and GluN2B (also known as Grin2b) CTDs in two knock-in mice and analyzed the mice's biochemistry, synaptic physiology, and multiple learned and innate behaviors. The eight behaviors were genetically separated into four groups, including one group comprising three types of learning linked to conserved GluN2A/B regions. In contrast, the remaining five behaviors exhibited subunit-specific regulation. GluN2A/B CTD diversification conferred differential binding to cytoplasmic MAGUK proteins and differential forms of long-term potentiation. These data indicate that vertebrate behavior and synaptic signaling acquired increased complexity from the duplication and diversification of ancestral GluN2 genes.

Tomás J Ryan,  et al.
Nature Neuroscience 16, 25–32 (2013) doi:10.1038/nn.3277

Synaptic scaffold evolution generated components of vertebrate cognitive complexity

The origins and evolution of higher cognitive functions, including complex forms of learning, attention and executive functions, are unknown. A potential mechanism driving the evolution of vertebrate cognition early in the vertebrate lineage (550 million years ago) was genome duplication and subsequent diversification of postsynaptic genes. Here the authors report the first genetic analysis of a vertebrate gene family in cognitive functions measured using computerized touchscreens. Comparison of mice carrying mutations in each of the four Dlg paralogs showed that simple associative learning required Dlg4, whereas Dlg2 and Dlg3 diversified to have opposing functions in complex cognitive processes. Exploiting the translational utility of touchscreens in humans and mice, testing Dlg2 mutations in both species showed that Dlg2's role in complex learning, cognitive flexibility and attention has been highly conserved over 100 million years. Dlg-family mutations underlie psychiatric disorders, suggesting that genome evolution expanded the complexity of vertebrate cognition at the cost of susceptibility to mental illness.
Jess Nithianantharajah, et al.
Nature Neuroscience 16, 16–24 (2013) doi:10.1038/nn.3276

Encoding asymmetry within neural circuits

Genetic and environmental factors control morphological and functional differences between the two sides of the nervous system. Neural asymmetries are proposed to have important roles in circuit physiology, cognition and species-specific behaviours. We propose two fundamentally different mechanisms for encoding left–right asymmetry in neural circuits. In the first, asymmetric circuits share common components; in the second, there are unique unilateral structures. Research in both vertebrates and invertebrates is helping to reveal the mechanisms underlying the development of neural lateralization, but less is known about the function of circuit asymmetries. Technical advances in the coming years are likely to revolutionize our understanding of left–right asymmetry in the nervous system.

Miguel L. Concha, et al.
Nature Reviews Neuroscience 13, 832-843 (December 2012) | doi:10.1038/nrn3371

Evolution of Human Intellect: Human-Specific Regulation of Neuronal Genes

A new study published November 20 in the open-access journal PLOS Biology has identified hundreds of small regions of the genome that appear to be uniquely regulated in human neurons. These regulatory differences distinguish us from other primates, including monkeys and apes, and as neurons are at the core of our unique cognitive abilities, these features may ultimately hold the key to our intellectual prowess (and also to our potential vulnerability to a wide range of 'human-specific' diseases from autism to Alzheimer's).

Science Daily, Nov 20, 2012

Hennady P. Shulha, et al.

PLoS Biology, 2012; 10 (11): e1001427 DOI:10.1371/journal.pbio.1001427

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

ENCODE Project Writes Eulogy For Junk DNA

SCIENCE VOL 337 7 SEPTEMBER 2012

30 research papers, including six in Nature and additional papers published by Science, sound the death knell for the idea that our DNA is mostly littered with useless bases. A decadelong project, the Encyclopedia of DNA Elements (ENCODE), has found that 80% of the human genome serves some purpose, biochemically speaking.