Review Articles in 2015

Aberrant epigenomes define many childhood and adult brain cancers, as demonstrated by widespread changes to DNA methylation patterns, redistribution of histone marks and disruption of chromatin structure. In this Review, the authors describe the convergence of genetic, metabolic and microenvironmental factors on mechanisms of epigenetic deregulation in brain cancer.

Tumor-associated macrophages (TAMs) establish a permissive microenvironment that positively influences glioma formation, progression and response to treatment. TAMs elaborate growth factors and cytokines that collectively facilitate tumor proliferation, survival and migration. Defining the distinct roles of these stromal cells in the glioma ecosystem may yield new opportunities for therapeutic targeting.

Reactive astrocytes have been proposed to become incompetent bystanders in epilepsy as a result of cellular changes rendering them incapable of performing housekeeping tasks. This review discusses new research that suggests that reactive astrocytes may drive the disease process by impairing the inhibitory action of neuronal GABA receptors.

Neurons receive synaptic input primarily onto their dendrites. This review focuses on how synaptic inputs are integrated by dendrites, with an emphasis on recent work in the intact brain. It describes the range of computations dendrites perform on their inputs, highlighting their critical role in information processing in the brain.

Measuring brain connections in humans continues to pose challenges despite the recent advances in MRI technology. The authors contrast methods used in humans with those used in animals and show the extent to which human techniques can inform us about connections despite their limitations.

In this Review, Hollon, Burgeno and Phillips discuss recent studies providing mechanistic insight into how stress alters circuitry involved in reward-related learning and motivation, as well as work examining how acute and chronic stress affect action selection in both rodents and humans.

The brain perceives and adapts to stressors via multiple interacting molecular mechanisms involving the cell surface, cytoskeleton and epigenetic regulation resulting in structural remodeling, with continually changing gene expression. Understanding mechanisms of plasticity and vulnerability facilitate development of intervention for anxiety and depressive disorders as well as age-related cognitive decline.

A mechanistic understanding of anxiety is required to advance the development of next-generation therapies for anxiety disorders. In this Review, Calhoon and Tye discuss recent insights into the circuit physiology driving anxiety-like behavior gained through the application of modern approaches in neuroscience.

Hodes et al. discuss mounting evidence in humans and rodent models of depression that causally links increased inflammation to depression. They take the perspective that heightened inflammation is a risk factor for depression and suggest targeted therapeutics to reduce inflammation as a novel approach to antidepressant treatment.

Severe stress impairs cognitive function, but enhances emotionality. This Review describes how stress triggers contrasting patterns of plasticity in the hippocampus, prefrontal cortex and amygdala, all brain areas that are involved in learning and memory. These features of stress-induced plasticity can have long-term consequences for the debilitating symptoms of stress-related disorders.

Research has revealed the molecular events that weaken connectivity in prefrontal cortical circuits during stress exposure. These events rapidly flip the brain from a reflective to reflexive state and may also contribute to degenerative changes in schizophrenia and Alzheimer's disease. This mechanistic understanding has translated to therapeutics for prefrontal disorders.

Environmental influences affect the brain and mental health and often are social or have social components, even the more complex societal or area-level exposures. This Review discusses the neural correlates of adverse and protective social influences and argues that innovative methods may provide ecologically more valid insights in social neuroscience.

In this review, Bale and Epperson discuss the importance of sex differences in stress found at all stages of life. As stress dysregulation is the most common feature across neuropsychiatric diseases, understanding sex differences in stress pathway development and maturation may predict disease risk and resilience factors across the lifespan.

The nature of the retinal computations of the direction of motion of visual stimuli has fascinated vision researchers for decades. In this Review, Borst and Helmstaedter discuss the most recent findings in the field, and draw parallels and point to differences in the circuitry of the mouse retina and the fly optic lobe from which such basic neuronal computation arises.

This Review article by Baljit Khakh and Michael Sofroniew discusses the latest progress in demonstration of molecular, cellular and functional heterogeneity of astrocytes in the central nervous system. The article highlights the way in which this diversity within and across astrocytes can affect normal function of the brain differently, and discusses pathological conditions where astrocyte heterogeneity is instrumental in manifesting various aspects of CNS dysfunction.

In this Review, Schneggenburger and Rosenmund discuss the molecular mechanisms that control the Ca²⁺ dependence of synaptic vesicle fusion during spontaneous and evoked modes of release at mammalian brain synapses. They argue that the same pool of vesicles is recruited during spontaneous and evoked release but at drastically different rates.

In the last 25 years, explosive interest has implicated the orbitofrontal cortex in nearly every function known to cognitive neuroscience. Yet scientific progress comes as much from questioning existing ideas as proposing new ones. This review discusses major theories of orbitofrontal function and the data that invalidate these ideas.

In this Review article, Jack Parent and Stewart Anderson discuss the advantages and limitations of using patient-derived cells, such as induced pluripotent stem cells, to probe the mechanisms of epileptogenesis and disease progression. In addition, they look at potential therapeutic avenues, such as cell-replacement strategies, that may arise from this field.

In this Review, Jeanne Paz and John Huguenard examine how recent work has informed us on the function of brain microcircuitry and how different circuit types may contribute to seizure generation and/or propagation. The authors also propose the idea that these microcircuits may regulate the spread of seizures and represent new targets for therapeutic intervention.

In this Review, Jeff Noebels examines recent advances in the identification of new genes underlying the onset of epilepsy. Given their functional convergence on synaptic inhibition and rich interactive landscape, collective analysis of genes driving major network interactions—as performed in the cancer field—may help point the way forward toward better diagnostics and target prioritization.