Volume 18 Issue 3, March 2015

Glial cell line-derived neurotrophic factor (GDNF) is in clinical trials for treating Parkinson's disease. However, endogenous GDNF function in brain catecholaminergic neurons has remained controversial. The authors utilized three complementary conditional knock-out approaches during development and adulthood and found that GDNF is not required for the maintenance of the catecholaminergic neurons in mice.

What drives us to pursue distant, more valuable goals over more proximate, lesser ones? Counter to what you might expect, this type of advanced goal-directed planning and foresight in primates may involve the amygdala. In a reward savings task, neurons in the amygdala track the length and subjective value of internally generated plans.

Cortical circuits are shaped by sensory experience. These changes have now been visualized with single-synapse resolution in vivo, revealing clustered potentiation along stretches of dendrite.

Neurofeedback that tracks attentional focus in real time using fMRI and alerts subjects to impending lapses by modulating the difficulty of the task itself has been demonstrated to improve behavioral performance.

Skilled behavior is thought to rely on the dorsal striatum. A study now reports that skills depend on striatal encoding of movement kinematics, linking learned sequences of movements with temporally distributed striatal activity.

Current treatment options are, for many patients with epilepsy, either insufficient or ineffective and, thus, new therapeutic methodologies are necessary. In this Perspective, Esther Krook-Magnuson and Ivan Soltesz look at recent advances in optogenetic-based modulation of circuit activity and seizures with an eye toward the prospect - and challenges - of utilizing these technologies for the treatment of epilepsy.

In this Perspective article, Brian Grone and Scott Baraban examine some of the numerous nonhuman animal models of epilepsy. The authors outline how traditional animal models have advanced our understanding of seizure initiation and epileptogenesis and also describe how the use of more 'non-traditional' model systems may further improve insight into both disease mechanisms as well as potential therapeutic avenues.

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.

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 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.

The term ‘seizure’ emphasizes the abrupt and unpredictable nature of the onset of epochs of pathological neuronal synchrony that define the disorder of epilepsy. Mechanisms of epilepsy should account for seizure transitions with these unique temporal properties. In this review, Kevin Staley discusses how combining insights from new genetic etiologies with seizure timing may begin to outline the mechanisms by which the brain becomes predisposed to seizures.

Using optogenetic manipulations and bioluminescence imaging of suprachiasmatic nucleus (SCN) firing rate, this study examines the interaction between molecular, electrical and behavioral circadian rhythms in mice. The study shows that alteration of clock neuron firing can reset molecular and behavioral circadian rhythms, and this effect required neuronal network interaction within the SCN. Thus, clock neuron spiking is fundamental to circadian pacemaking as both an input to and output of the neuronal network responsible for circadian behavior.

This study shows that cocaine strengthens glutamatergic transmission, reduces K⁺ channel function and drives hyperexcitability in lateral habenula neurons projecting to the rostromedial tegmental nucleus. The authors also show that GluA1 trafficking mediates these cellular modifications and is instrumental in a drug-mediated depressive-like phenotype.

microRNAs control synaptic signaling through regulation of postsynaptic responsiveness. This study provides evidence that the conserved microRNAs miR-1000 and miR-137 act presynaptically via glutamate transporters to regulate glutamate release. miR-1000 expression is activity dependent, perhaps allowing activity to fine-tune the strength of excitatory synaptic transmission.

Dopamine axons projecting from the ventral tegmental area to the nucleus accumbens (mesoaccumbens axons) play a role in motivation. Tthe authors show that there are distinct microdomains releasing either dopamine or glutamate within individual mesoaccumbens axons in rats and mice.

Neurogliaform interneurons constitute an essential component of cortical circuits. This paper provides evidence that, during early development, superficial neurogliaform cells of the primary somatosensory barrel field cortex receive prominent innervation from the thalamus. These afferents also activate postsynaptic NR2B-containing NMDA receptors, which are essential for the neurons' proper cortical integration.

Insertion of AMPA receptors into the synaptic membrane is thought to be a central mechanism for controlling experience-dependent changes in synaptic strength, yet this has never been observed in real time in the intact brain. Using two-photon imaging, Zhang and colleagues were able to provide this missing piece of information by tracking the insertion of GluA1 in spines in mouse barrel cortex neurons during repetitive whisker stimulation.

The authors investigated the role of glycinergic preBötC neurons in respiratory rhythmogenesis in mice using viral delivery of Channelrhodopsin-2 (ChR2) or Archaerhodopsin (Arch) genes. They conclude that glycinergic preBötC neurons modulate inspiratory pattern and are important for reflex apneas but that the rhythm can persist after significant dampening of their activity.

Comprehensive analysis of epigenetic regulation demonstrates a series of complex, interacting chromatin mechanisms by which chronic exposure to opiates downregulates Bdnf gene transcription in the ventral tegmental area. This regulatory cascade is also shown to play a role in controlling opiate-induced behavioral plasticity.

The authors show that astrocytes produce high levels of the adenosine receptor A2A in Alzheimer brains. Reducing the levels of astrocytic A2A boosted memory in young and aging mice and mouse models of Alzheimer disease, whereas activating a related molecular pathway impaired memory. Thus, astrocytes regulate memory and abnormal receptor activity in these cells may contribute to memory disorders.

Enhanced NMDA receptor function and social interaction deficits are observed in mice lacking the excitatory postsynaptic scaffolding protein IRSp53. Reducing NMDAR activity by pharmacological methods rescues the impaired social interaction observed in these mice. This suggests that enhanced NMDA receptor function may be associated with social deficits.

Coincidence detection is a fundamental neural operation, developed to an extreme in the computation of interaural time differences for sound localization. This study utilizes intracellular in vivo recordings and pharmacological manipulations in the medial superior olive of Mongolian gerbil to reveal that maximal coincidence is not just determined by the timing of synaptic inputs, but also by intrinsic neural properties.

The authors recorded spiking activity in the sensorimotor striatum of rats performing a motor sequence in an automatic manner. They report continuous and integrative representation of contextual and kinematic information. Reversible perturbation of these representation increased execution variability, suggesting a strong contribution in constraining the execution motor habits.

Combining single-neuron recordings and a multistep economic choice task in monkeys, the authors find activity in amygdala neurons that predicts the value and length of an internally planned choice sequence leading to future reward. Prospective amygdala activity appears to encode components of an internal plan and guide behavior over several steps towards self-defined, distant goals.

Lapses of attention are commonplace, potentially because they are detected too late to be prevented. The authors use real-time fMRI to provide participants continuous access to their attentional state. Real-time feedback, particularly from frontoparietal cortex, improved sustained attention abilities and modified representations in visual cortex and basal ganglia.

Nature Neurosciencepresents a special focus issue on the topic of Epilepsy which, through a series of reviews and opinionated articles from key leaders in the field, aims to highlight many of the most recent and informative research which has expanded our understanding of the pathogenic events which lead to aberrant brain activity and the molecular and circuit-level mechanisms that regulate neuronal excitability.