Volume 19 Issue 4, April 2016

A study reports mutations in a histone methyltransferase gene, SETD1A, in schizophrenia patients and demonstrates that tens of thousands of people must be screened to provide robust evidence of a gene's involvement in schizophrenia.

Inhibitory optogenetic tools prevent action potential generation during illumination. A study explores the possibility of squelching already propagating action potentials locally at axon terminals before they trigger neurotransmitter release.

Master circadian clocks in discrete neurons trigger profound daily changes in brain states, such as sleep and wake states. A study now finds a circuit through which these pacemakers act to control daily behavioral rhythms in Drosophila.

Discrimination of neutral from harmful environments is important for survival. But how do salient contextual signals yield persisting memories? A study uncovers a circuit that increases the specificity of hippocampus-based memories.

In this Perspective, Murray Sherman discusses connectivity in the thalamocortical system, including the evidence that cortical areas are connected in parallel by direct and transthalamic pathways. Because thalamus receives inputs that form collaterals with subcortical motor regions, the author suggests that it may relay efference copy information.

In this Review, a collaboration of leading experts in amyotrophic lateral sclerosis (ALS) research present the state of the field regarding the use patient-derived induced pluripotent stem cells to generate motor neurons in vitro. Motor neuron characterization, including transcriptomics, molecular markers, neuron function and electrophysiology, are discussed in the context of maturation and disease.

Optogenetic inhibition of specific axonal projections is a potentially powerful technique for assessing defined neural pathways’ contributions to behavior. The authors report that while optogenetic inhibition can efficiently attenuate presynaptic release, it can under some conditions lead to undesired effects such as depolarization and increased spontaneous release.

Pathogenesis for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) remains largely unknown. Using a mouse model of ALS and FTD, the authors found that somatostatin interneurons in motor cortex were hyperactive. This hyperactivity led to the disinhibition of pyramidal neurons and correlated with signs of excitotoxicity. Ablating somatostatin interneurons restored the excitability of pyramidal cells to a normal level and prevented neurodegeneration.

Dopaminergic neurons in the ventral tegmental area (VTA) contribute to mediating stress susceptibility and resilience. The authors demonstrate that noradrenergic neurons in the locus coeruleus can drive the activity of these dopaminergic VTA neurons to generate a resilient response to chronic stress.

Subsets of hippocampal neurons store map-like representations of experienced environments. The authors optogenetically silenced a neuronal population active in an environment and saw an alternative map emerge. In a cocaine-paired environment, this approach neutralized drug-place preference, implicating recoding of spatial memory engrams as strategy for alleviating maladaptive behaviors.

Increases in synaptic inhibition have been proposed to underlie divisive normalization in distal neural networks. Here, using optogenetic stimulation and intracellular recordings in mouse visual cortex, the authors argue that normalization is a result of a decrease in synaptic excitation.

The authors analyzed the whole-exome sequences of over 16,000 individuals and found that very rare variants predicted to disrupt the SETD1A gene confer substantial risk for schizophrenia. Damaging variants in SETD1A were also associated with diverse, severe developmental disorders, providing an important genetic link between schizophrenia and other neurodevelopmental disorders.

The authors report the generation of fluorescent false neurotransmitter 200 (FFN200), a new optical probe for selectively monitoring monoamine exocytosis in cultured neurons and brain slices. Using the new tool in combination with Ca²⁺ imaging, they find functionally silent dopaminergic vesicle clusters in the striatum, with impaired exocytosis at a step downstream from Ca²⁺ influx.

Circadian pacemaker neurons help animals synchronize their behavior with 24-hour day–night cycles. The authors identify a neuronal circuit that links Drosophila pacemaker neurons to locomotor activity and sleep centers. They show that the intrinsic neuronal activity rhythms of pacemaker neurons are transmitted through this circuit to generate rhythmic behavior.

The authors show that the ventrolateral aspect of the ventromedial hypothalamus (VMHvl), a region previously implicated in attack behavior, can also drive flexible aggression-seeking behavior. When male mice learn a task to seek out attack opportunities, activity in the VMHvl tracks and bidirectionally modulates the seeking behavior that leads to future attack.

This study demonstrates that fear memory expression is driven by 4-Hz oscillations in prefrontal–amygdala circuits. During fear behavior, prefrontal 4-Hz oscillations lead amygdala and synchronize spiking activity between the two structures. Ultimately, this study identifies 4-Hz oscillations as a physiological signature of fear memories.

This study shows that the amount of linearly decodable information for categorical-orthogonal object tasks (for example, position, scale, pose, perimeter and aspect ratio) increases up the ventral visual hierarchy, ultimately matching human levels in inferior temporal cortex. It also provides a computational model that explains how this pattern of information arises.

To gain insight into how mutant huntingtin (mHtt) CAG repeat length modifies Huntington's disease pathogenesis, the authors profiled mRNA in over 600 brain and peripheral tissue samples from Huntington's disease knock-in mice with increasing CAG repeat lengths. Coexpression network analyses reveal 13 striatal and 5 cortical modules that are highly correlated with CAG length and age.

Silicon microelectrodes are a powerful technique for recording neuronal population activity. Increases in probe size and density make for larger recordable populations, but also require new techniques for processing the resulting data. The authors describe a suite of practical, open source software for spike sorting of large, dense electrode arrays.