Articles in 2017

Using an adeno-associated virus–mediated, direct in vivo CRISPR screen, the authors mapped a quantitative landscape of glioblastoma suppressors. Their study revealed gene combinations that functionally drive gliomagenesis from normal glia in native mouse brains. The authors further demonstrate that mutational background can differentially influence gene expression and chemotherapeutic resistance.

The authors propose a framework for drug repositioning by comparing GWAS-imputed transcriptomes with drug-induced gene expression profiles. The approach was applied to seven psychiatric disorders. Repositioning candidates were significantly enriched for known psychiatric medications or for therapies considered in clinical trials, supporting a role of GWAS in guiding drug discovery.

New techniques for visually stimulating and stabilizing the retina reveal that humans control covert attentional resources with high precision at the center of gaze. These findings show that fine attentional deployment occurs within the fovea and enhances high-acuity vision.

Antipsychotic treatment in patients with schizophrenia often reduces hallucinations and delusions, but cognitive deficits that impair performance of everyday activities may persist or worsen. Our findings reveal a mechanism by which increased NF-κB activity leads to increased HDAC2 levels, impairing synaptic plasticity and memory during prolonged antipsychotic treatment.

The authors address why the use of prior expectations might be compromised in autism, by using computational models and pupillometric markers of the neuromodulator noradrenaline. They show that by estimating the world to be more changeable than it really is, adults with autism have difficulty in learning what to expect.

Although the hippocampus has long been linked to planning, it has not been shown to be necessary for planning behavior. Using computational modeling and a new rat task that allows the quantification of planning behavior across many repeated trials, the authors report the first evidence that hippocampal inactivation impairs planning.

The mechanisms underpinning neuronal death in Alzheimer's disease (AD) remain unclear. Caccamo and colleagues show that necroptosis contributes to neurodegeneration in AD. Blocking necroptosis reduced neuronal loss in a mouse model of AD, suggesting that necroptosis might be a therapeutic target in AD.

Yates and colleagues statistically dissect MT and LIP responses during motion discrimination. They show decreasing temporal weighting of motion in MT, consistent with psychophysical weighting, and show that LIP spikes encode the upcoming choice more than integrated motion or simultaneously recorded MT spikes, suggesting an indirect relationship between these areas.

An expanded repetition of a DNA sequence within the C9orf72 gene is the most common genetic cause for motor neuron disease and frontotemporal dementia. In this study, the authors show that this expansion causes increased genomic breaks and reduces the cell's ability to repair the breaks, ultimately leading to neuronal cell death.

Survey of postzygotic mosaic mutations (PZMs) in 5,947 trios with autism spectrum disorders (ASD) discovers differences in mutational properties between germline mutations and PZMs. Spatiotemporal analyses of the PZMs also revealed the association of the amygdala with ASD and implicated risk genes, including recurrent potential gain-of-function mutations in SMARCA4.

The mechanistic basis of how novel stimuli become familiar with repeated exposures has remained elusive. Molas et al. demonstrate that familiarity activates the interpeduncular nucleus, thereby reducing motivation to explore. Familiarity signaling in the interpeduncular nucleus is bidirectionally modulated by habenula and ventral tegmental area afferents to control novelty preference.

The authors show that transcranial magnetic disruption of the right temporoparietal junction decreases strategic behavior during competitive interactions. The altered behavior relates to neural activity changes both locally and in interconnected prefrontal areas. These brain networks may causally underlie the ability to predict the behavior of other agents.

A fundamental goal of learning is to establish neural patterns that cause desired behaviors. This paper demonstrates that sleep-dependent processing is required for credit assignment and the establishment of task-related activity reflecting the causal neuron-behavior relationship. Decoupling of spiking to sleep slow oscillations using optogenetics methods disrupted this process.

Corticospinal cells of the motor cortex act as a direct link between the cortex and movement-generating circuits within the spinal cord. The authors demonstrate that the relationship between activity of these cells and movement changes with time and learning, indicating a flexible cortical output to drive movements.

Using in vivo calcium imaging in a mouse model of neuropathic pain, the authors found a persistent increase in the activity of somatosensory cortex pyramidal neurons following peripheral nerve injury. Repeated pharmacogenetic activation of somatostatin-expressing inhibitory neurons after injury not only corrected this abnormal cortical activity but also prevented the development of chronic pain.

Strong genetic evidence points to a significant role for heterozygous mutations to general chromatin remodeling factors, such as CHD8, in autism. Gompers et al. combine genomic, neuroanatomical and behavioral approaches to present an initial integrative picture of transcriptional mechanisms and widespread impacts of Chd8 haploinsufficiency across brain development in mice.

The authors identified a protective genetic allele associated with lower PU.1 (SPI1) expression in myeloid cells by conducting a genome-wide scan of Alzheimer's disease (AD). PU.1 binds the promoters of AD-associated genes (e.g., CD33, MS4A4A & MS4A6A, TYROBP) and modulates their expression, suggesting it may reduce AD risk by regulating myeloid cell gene expression.

This study characterizes the properties of disease-causing mutations that produce sporadic amino acid replacements in proteins of people with autism and developmental delay. The mutations tend to cluster and reoccur at specific regions important to protein function, highlighting for future follow-up ∼200 candidate genes, many involved in neuronal signaling.

Combining electrophysiology and computational modeling, the authors show that the dendrites of entorhinal cortex stellate and pyramidal cells are electrically excitable and that this improves the robustness of grid cell firing. The results suggest that active dendrites are critical for spatial navigation, a fundamental computation in the brain.

The precise mechanisms that cause human obesity remain unknown. Here the authors illustrate how increased expression of Cadm1, a mediator of synapse assembly, is relevant to weight gain. Reduction of Cadm1 in multiple brain regions promoted weight loss, and these observations provide insight into the neuronal pathways contributing to obesity.