giovedì 26 giugno 2014

Nature Neuroscience, Neurogenomics – 4

Copertina vol. 17, n. 6, giugno 2014
di Alberto Carrara, LC
Coordinatore del Gruppo di Neurobioetica (GdN) e
Fellow della Cattedra UNESCO in Bioetica e Diritti Umani

Dopo aver presentato la copertina (ricordo che l’immagine è opera di Alexander Arguello) e aver riportato l’editoriale in lingua originale (inglese) dell’ultimo numero della rivista Nature Neuroscience dedicato alla frontiera emergente delle neuroscienze, la neurogenomica, oggi mi propongo presentarvi una sintesi dei contenuti della rivista, mentre prossimamente commenterò l’editoriale intitolato Focus on neurogenomics.

Oggigiorno, centinaia di regioni lungo il genoma vengono correlate a disordini riguardanti il cervello”....

È questo un primo dato di fatto che emerge dall’interazione e dal dialogo profiquo tra genomica e neuroscienze, comprendenti discipline classiche quali la neurologia, ma anche la psichiatria, disciplina quest’ultima, posta sotto i riflettori e sempre più chiamata a fornire risposte terapeutiche ai numerosi pazienti, spesso deboli, emarginati o resi “anonimi” in una società individualistica che fa fatica a “scoprire” la sofferenza e il dolore psichico del prossimo...

La mole di dati forniti dalla ricerca genetica in ambito psichiatrico e neurologico costituisce un “tesoro” spesso però difficile da abbordare. Non è facile “navigare” all’interno di questi dati e, soprattutto, tradurli in innovazioni biologiche o tecnologiche a servizio della prassi clinica. È questa la sfida di oggi!

In questo numero speciale di Nature Neuroscience sulla neurogenomica, vengono presentate una serie di prospettive e recensioni dei maggiori esperti mondiali sulle ultimissime metodiche genomiche, le loro recenti scoperte nell’ambito della psichiatria e della neurologia e le loro implicazioni ed applicazioni alle neuroscienze.

I contenuti di questa sezione monografica dedicata alla neurogenomica sono i seguenti.

Editorial - Focus on neurogenomics p.745, doi:10.1038/nn.3735
Nature Neuroscience presents a series of Perspectives and Reviews highlighting recent advances in understanding the genetics of complex brain disorders.

News and Views
Shedding light on learning pp.746–747, Byron M Yu & Steven M Chase, doi:10.1038/nn.3723.
Brain-computer interfaces (BCIs) and optical imaging have both undergone impressive technological growth in recent years. A study in which mice learn to modulate neural activity merges these technologies to investigate the neural basis of BCI learning with unprecedented spatial detail.

Impaired import: how huntingtin harms pp. 747–749, Elizabeth A Jonas, doi:10.1038/nn.3726.
We now learn that mutant huntingtin binds to a complex that imports constituent proteins across the mitochondrial inner membrane, halting bioenergetics in synaptic mitochondria and predisposing to neuronal dysfunction and death.

Is there signal in the noise? pp.750–751, Alexander S Ecker & Andreas S Tolias, doi:10.1038/nn.3722.
A study now shows that variability in neuronal responses in the visual system mainly arises from slow fluctuations in excitability, presumably caused by factors of nonsensory origin, such as arousal, attention or anesthesia.

The needle in the haystack pp.752–753, Clarissa J Shephard & Garrett B Stanley, doi:10.1038/nn.3730.
Spike-based approaches to feature selectivity in sensory pathways can bias toward only the most active neurons. A subthreshold method identifies feature selectivity in the rodent vibrissal system regardless of spiking activity.

The (gamma) power to control our dreams pp.753–755, Jessica D Payne, doi:10.1038/nn.3727.
Stimulating the brain in the gamma frequency range, which is the frequency band most often associated with conscious awareness in the awake state, boosts the ability to engage in lucid dreaming during REM sleep.

Pacemaker's burden p.755, Min Cho, doi:10.1038/nn0614-755

Perspective
Focus on Neurogenomics
Genome-scale neurogenetics: methodology and meaning pp.756–763, Steven A McCarroll, Guoping Feng & Steven E Hyman, doi:10.1038/nn.3716.
Large-scale collaborative efforts coupled with new genomic technologies now allow reliable detection of genetic variants influencing risk for major psychiatric and neurodevelopmental disorders. In this Perspective the authors provide a primer on current genome-wide efforts to identify risk variants and how these may be translated into neurobiological insights.

Reviews
Focus on Neurogenomics
Prioritization of neurodevelopmental disease genes by discovery of new mutations pp.764–772.
Alexander Hoischen, Niklas Krumm & Evan E Eichler, doi:10.1038/nn.3703.
Advances in genome sequencing technologies have revolutionized the search for rare and penetrant mutations leading to diseases such as autism. Given that all individuals carry new and disruptive mutations, in this Review, the authors discuss ways to home in on pathogenic mutations associated with neurodevelopmental disorders.

One gene, many neuropsychiatric disorders: lessons from Mendelian diseases pp.773–781, Xiaolin Zhu, Anna C Need, Slavé Petrovski & David B Goldstein, doi:10.1038/nn.3713.
Mutations in Mendelian disease genes often lead to distinct clinical presentations, and the same non-specific risk is now apparent for many neuropsychiatric disorders. In this Review, the authors analyze pathogenic mechanisms for known Mendelian disease and discuss what it means for understanding the causes of non-specific genetic risk in more complex brain diseases.

Large-scale genomics unveils the genetic architecture of psychiatric disorders pp. 782–790, Jacob Gratten, Naomi R Wray, Matthew C Keller & Peter M Visscher, doi:10.1038/nn.3708.
It is now possible to systematically identify, on a genome-wide scale, genetic variants for disease, how often they occur in the population and how large their impact is on risk. In this Review, the authors discuss recent findings regarding the genetic architecture of psychiatric disorders and the contribution of common but weak and rare but strong variants to disease risk.

Whole-genome analyses of whole-brain data: working within an expanded search space pp.791–800, Sarah E Medland, Neda Jahanshad, Benjamin M Neale & Paul M Thompson, doi:10.1038/nn.3718.
Understanding how genetic variation contributes to normal and pathological brain function requires integrating genetic and neuroimaging studies. New imaging consortia now make it possible to systematically assess the impact of genetic variation on the structure and function of the brain on a whole-genome and whole-brain level. In this Review, the authors summarize efforts to combine genome-wide studies with brain imaging and discuss the statistical and methodological issues necessary to insure rigor and robustness in this rapidly developing field.

Brief Communications
The age and genomic integrity of neurons after cortical stroke in humans pp. 801–803, Hagen B Huttner, Olaf Bergmann, Mehran Salehpour, Attila Rácz, Jemal Tatarishvili, Emma Lindgren, Tamás Csonka, László Csiba, Tibor Hortobágyi, Gábor Méhes, Elisabet Englund, Beata Werne Solnestam, Sofia Zdunek, Christian Scharenberg, Lena Ström, Patrik Ståhl, Benjamin Sigurgeirsson, Andreas Dahl, Stefan Schwab, Göran Possnert, Samuel Bernard, Zaal Kokaia, Olle Lindvall, Joakim Lundeberg & Jonas Frisén, doi:10.1038/nn.3706.
In this study, the authors use measures of carbon-14 in neuronal DNA from human stroke patient cortical tissue samples to show that, unlike previous studies done in rodents, they do not find any evidence of increased neurogenesis after an ischemic injury. In addition, DNA damage assays suggest that there is no increase in DNA rearrangement after this insult.

Cellular origins of auditory event-related potential deficits in Rett syndrome pp. 804–806, Darren Goffin, Edward S Brodkin, Julie A Blendy, Steve J Siegel & Zhaolan Zhou, doi:10.1038/nn.3710.
Sensory processing deficits are observed in individuals with Rett syndrome and MeCP2-deficient mice. Here, the authors show that it is the loss of MeCP2 specifically in forebrain inhibitory neurons that leads to deficits in auditory-evoked local field potentials and elicits the seizures observed in MeCP2-deficient mice.

Volitional modulation of optically recorded calcium signals during neuroprosthetic learning pp.807–809
Kelly B Clancy, Aaron C Koralek, Rui M Costa, Daniel E Feldman & Jose M Carmena, doi:10.1038/nn.3712.
In this paper, Clancy and colleagues introduce an optically driven brain machine interface (BMI) based on the processing of optical calcium signals recorded using two-photon microscopy. When applied to mouse cortex, this approach revealed that learning in a BMI-mediated operant task is accompanied by the progressive spatial refinement of activity in local networks comprising output-relevant neurons.

Induction of self awareness in dreams through frontal low current stimulation of gamma activity – pp.810–812, Ursula Voss, Romain Holzmann, Allan Hobson, Walter Paulus, Judith Koppehele-Gossel, Ansgar Klimke & Michael A Nitsche, doi:10.1038/nn.3719.
Lucid dreaming, in which the sleeper is aware of the dream state, has been associated with increased neural activity around 40 Hz (lower gamma band), but their causal relationship remains unclear. The authors show that, during REM sleep, fronto-temporal transcranial stimulation in the lower gamma band can induce lucid dreaming.

Articles
Aberrant topoisomerase-1 DNA lesions are pathogenic in neurodegenerative genome instability syndromes – pp.813–821, Sachin Katyal, Youngsoo Lee, Karin C Nitiss, Susanna M Downing, Yang Li, Mikio Shimada, Jingfeng Zhao, Helen R Russell, John H J Petrini, John L Nitiss & Peter J McKinnon, doi:10.1038/nn.3715.
In this study, the authors show that topoisomerase-1–DNA cleavage complex (Top1cc) accumulation may be involved in the onset of ataxia telangiectasia and spinocerebellar ataxia with axonal neuropathy 1. In addition, they find that ATM regulates Top1cc levels in a kinase activity– and double-stranded break repair–independent manner.

Inhibition of mitochondrial protein import by mutant huntingtin – pp.822–831, Hiroko Yano, Sergei V Baranov, Oxana V Baranova, Jinho Kim, Yanchun Pan, Svitlana Yablonska, Diane L Carlisle, Robert J Ferrante, Albert H Kim & Robert M Friedlander, doi:10.1038/nn.3721.
Mitochondrial dysfunction has been associated with Huntington's disease. The authors show that mutant huntingtin binds to the mitochondrial import protein TIM23, leading to a deficit in import. Overexpression of TIM23 subunits partially rescued the import defect and subsequent neuronal death.

Mitochondrial oxidant stress in locus coeruleus is regulated by activity and nitric oxide synthase – pp.832–840, Javier Sanchez-Padilla, Jaime N Guzman, Ema Ilijic, Jyothisri Kondapalli, Daniel J Galtieri, Ben Yang, Simon Schieber, Wolfgang Oertel, David Wokosin, Paul T Schumacker & D James Surmeier, doi:10.1038/nn.3717.
Noradrenergic neurons in the locus coeruleus (LC) are known to undergo degeneration in Parkinson's and Alzheimer's diseases. LC neurons may be under bioenergetic constraints due to spontaneous spiking. Here, Sanchez-Padilla et al. show that calcium entry through L-type channels during spiking of LC neurons creates mitochondrial oxidant and nitrosative stress. The study also demonstrates increased LC vulnerability in a mouse model of Parkinson's disease.

Scaling down of balanced excitation and inhibition by active behavioral states in auditory cortex – pp.841–850, Mu Zhou, Feixue Liang, Xiaorui R Xiong, Lu Li, Haifu Li, Zhongju Xiao, Huizhong W Tao & Li I Zhang, doi:10.1038/nn.3701.
The authors report that in mouse auditory cortex, the sensory-evoked spike responses of layer 2/3 (L2/3) excitatory cells were scaled down with preserved sensory tuning when animals transitioned from quiescence to active behaviors, while L4 and thalamic responses were unchanged. This laminar-specific gain control could be attributed to an enhancement of L1-mediated inhibition.

Population code in mouse V1 facilitates readout of natural scenes through increased sparseness – pp.851–857, Emmanouil Froudarakis, Philipp Berens, Alexander S Ecker, R James Cotton, Fabian H Sinz, Dimitri Yatsenko, Peter Saggau, Matthias Bethge & Andreas S Tolias, doi:10.1038/nn.3707.
The authors recorded populations of up to 500 neurons in the mouse primary visual cortex during natural movies. They found that higher-order correlations in natural scenes induce a sparser code, with reliable activation of a smaller set of neurons that can be read out more easily, but only in anesthetized and active awake animals, not during quiet wakefulness.

Partitioning neuronal variability – pp.858–865, Robbe L T Goris, J Anthony Movshon & Eero P Simoncelli, doi:10.1038/nn.3711.
The authors developed a model of neuron firing in which spike generation arises from the combination of sensory drive and stimulus-independent modulatory influences. This model provides an accurate account of neuron responses in multiple visual areas, suggesting that variability originates from excitability fluctuations that increase in strength along the visual pathway.

Spatiotemporal receptive fields of barrel cortex revealed by reverse correlation of synaptic input – pp. 866–875, Alejandro Ramirez, Eftychios A Pnevmatikakis, Josh Merel, Liam Paninski, Kenneth D Miller & Randy M Bruno, doi:10.1038/nn.3720.
To investigate the sensory contributions of barrel cortex, the authors estimate spatiotemporal receptive fields by reverse correlation of multi-whisker stimulation to synaptic inputs. Complex stimuli revealed dramatically sharpened receptive fields, largely due to adaptation, and suggest the potential importance of surround facilitation through adaptation for discriminating complex shapes and textures during natural sensing.

Executive control processes underlying multi-item working memory– pp.876–883, Antonio H Lara & Jonathan D Wallis, doi:10.1038/nn.3702.
The authors recorded activity of prefrontal cortex neurons in monkeys performing a multi-item color change detection task and found that neurons reported information about the item's position and the location covert attention, but not its color. Increased power in the local field potential correlated with more precise color representations. Taken together, these results suggest that PFC controls the allocation of resources in working memory.

Technical Report
High-fidelity optical reporting of neuronal electrical activity with an ultrafast fluorescent voltage sensor – pp.884–889, François St-Pierre, Jesse D Marshall, Ying Yang, Yiyang Gong, Mark J Schnitzer & Michael Z Lin, doi:10.1038/nn.3709.

In this technical report, St-Pierre and colleagues introduce a new genetically encoded voltage sensor called Accelerated Sensor of Action Potentials 1 (ASAP1), which consists of a circularly permuted GFP inserted in the extracellular voltage-sensing domain of a phosphatase. ASAP1 surpasses existing sensors in reliably detecting single action potentials and tracking subthreshold potentials and high-frequency spike trains.

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