Volume 16 Issue 5, May 2013

A study in this issue suggests that neuronal DNA double-strand breaks can result from natural behaviors. The breaks occur in the circuits that are activated and are enhanced in a model of Alzheimer's disease. The implications of this finding are far-reaching.

Cognitive function declines as part of the normal aging process. A study finds that the dopamine-boosting drug L-DOPA changes value representation in the brain and improves reinforcement learning in older individuals.

What makes certain individuals more vulnerable to drug abuse than others? A study finds that potentiation of glutamatergic inputs to nucleus accumbens indirect pathway neurons may protect against compulsive drug-seeking.

A screen now identifies a protein that regulates degradation of mutant huntingtin, which causes Huntington's disease, and manipulations show that promoting clearance of the toxic protein itself may be sufficient to halt disease.

In this study, the authors show that a sodium/solute co-transporter–like protein, SLC5A11, is expressed in a subset of R4 ellipsoid body neurons in Drosophila and is involved in the detection of the nutritive value of sugars. Flies that lack functional SLC5A11 exhibit sugar preference on the basis of concentration.

In this study, the authors show that transposable element activity increases in the Drosophila brain with advancing age. Mutating the Drosophila Argonaute 2 (Ago2) gene exacerbated age-related transposable element activity and led to impaired memory and shortened lifespan.

Wang et al. find that deletion of FIP200, a protein essential for autophagy, leads to deficits in the maintenance and differentiation of postnatal neural stem cells (NSC). These effects are rescued by an antioxidant treatment, suggesting that FIP200-mediated autophagy regulates neurogenesis by controlling the oxidative state of NSC.

In this study, the authors show that layer V projection neurons require the presence of subcortical CX3CR1-positive microglia for survival. IGF1 secretion from these microglia appears to be necessary for this trophic effect. Inhibition of the microglial cell activation abrogates IGF1 secretion and compromises neuronal survival.

BAF53b is a neuron-specific component of the nucleosome remodeling complex mSWI/SNF that allows euchromatin formation and provides epigenetic regulation of gene expression. Here, the authors generated BAF53b mutant and rescue mice to show that postnatal nucleosome modeling is crucial to hippocampal synaptic plasticity, neuronal morphology and memory performance.

The authors performed a genome-wide RNAi screen for genes modifying mutant Huntingtin (mHTT) clearance, identifying NUB1 as a protein whose overexpression lowered mHTT protein amounts, rescued mHTT-induced neuronal death and improved motor function in a Drosophila model of Huntington's disease. NUB1 promoted polyubiquitination and proteasomal degradation of mHTT.

Oligodendrocytes form myelin sheaths and provide metabolic support to axons. Using in vivo genetic fate tracing in a mouse model of amyotrophic lateral sclerosis (ALS), this study shows that there is extensive degeneration of oligodendrocytes near motor neurons prior to behavioral manifestation of disease. Although oligodendrocytes were regenerated from resident progenitors, they failed to mature and restore myelin, a feature also observed in brain and spinal cord tissue from ALS patients. Selective deletion of ALS-linked mutant SOD1 from the oligodendrocyte lineage greatly delayed disease onset, suggesting that this mutant protein impairs their ability to support motor neurons.

The authors use in vivo imaging to examine astrocyte dynamics after a cortical injury over the course of several weeks. They reveal a heterogeneity in astrocyte responses and show that astrocytes do not migrate toward the injury site, but instead proliferate in the juxtavascular region.

Relative amounts of amyloid-β peptides of different length are altered in the brains of Alzheimer's disease patients. Here the authors show that neuronal patterns differentially regulate the production of amyloid-β isoforms by modifying the molecular conformation of presenilin-1, the catalytic subunit of γ-secretase that cleaves amyloid precursor protein to release amyloid-β.

Wamsteeker Cusulin and colleagues report that stress-induced glucocorticoid release can trigger metaplasticity at GABAergic synapses on neuroendocrine neurons of the hypothalamus in rodents. Following stress, these GABAergic synapses gain the ability to undergo long-term depression in vitro, which involves amplification of mGluR signaling and retrograde suppression of synaptic transmission via persistent activation of presynaptic μ-opioid receptors. This form of plasticity may serve as a mechanism for behavioral stress adaptation.

Inoue and colleagues find that stress triggers a noradrenaline-dependent metaplastic change at GABAergic synapses onto paraventricular neurons of the hypothalamus in rodents. This metaplasticity depends on mGluR1, enables these synapses to undergo long-term potentiation during afferent bursts stimulation in vitro and possibly contributes to the neuroendocrine sensitization to stress.

In this study, the authors show that neuronal activity, induced by natural exploration, exposure to visual stimuli or optogenetic probe–mediated stimulation, can induce double-stranded DNA breaks (DSBs) in neurons. The numbers of these DSBs were aggravated in the presence of amyloid precursor protein and depended on extrasynaptic NMDAR activity.

Touch information is conveyed by a receptorless whisker hair to the follicle mechanoreceptors that provide input to the brain. Here the authors show that information processing goes on even at the level of the whisker, which suggests a role for pre-neuronal morphological computation in active vibrissal touch.

The authors show that the strengthening of excitatory inputs onto nucleus accumbens D2 medium spiny neurons (D2-MSNs) correlates with a weak motivation to self-administer cocaine in mice. Silencing or activating D2-MSNs enhances or suppresses the motivation to self-administer cocaine, respectively, suggesting that this pathway constrains compulsive drug seeking behaviors.

How are goal-directed actions directed and motivated? This paper presents behavioral and electrophysiological data in rats to dissect the differential role of the ventral striatum (VS) and dorsomedial striatum (DMS) in action-selection and motivation. The work suggests that the DMS is important in encoding the net expected return, sensitizing the rats to the local average reward value in a block of trials.

Senescence degrades reward-based decision-making. Here the authors show that there are abnormalities in older adults in a functional magnetic resonance imaging measure of reward prediction error (RPE) signaling and changes in the structural connectivity of areas encoding reward value information. Administration of levodopa ameliorated behavioral deficits and restored RPE signaling in some older adults.