Volume 17 Issue 6, June 2014

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Advances in genomics is accelerating the pace of discovery in all areas of biology and medicine including psychiatry. Neuroscientists are now inundated with information implicating hundreds of regions across the genome that harbor rare and common risk variants for disorders of the brain. Navigating this data deluge and translating it into biological and mechanistic insights remains a formidable challenge. In this special Nature Neuroscienceissue on neurogenomics, we present a series of perspectives and reviews by leading experts on the latest genomic methods, their recent discoveries in psychiatry and neurology and their implication for and application to neuroscience.