To understand the brain, theoretical and experimental approaches must be integrated to make sense of the enormous amount of existing data, and to guide future experiments. In this issue, we present a special focus on computational and systems neuroscience. Along with commissioned perspectives, the focus contains primary research articles featuring the best work presented at Cosyne, a meeting that brings together a diverse group of theoretical and experimental neuroscientists. Image of glass brain courtesy of Bret Lobree. (pp 1643-1656 and 1667-1711)

Addiction is pervasive, affecting millions of people around the world. The progression from recreational drug use to drug dependence and addiction is influenced by many factors, including the nature of the drug, the personality of the user, and environmental stressors. In this issue, we present reviews and opinion pieces on the neurobiology of drug abuse, decision making and habit formation, as well as a commentary on how the neuroscience of addiction should guide public policy and treatment. This special focus is sponsored by the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism. (pp 1427-1489)

A new report from Hefft and Jonas shows that whereas parvalbumin-containing interneurons in the rat hippocampus release GABA in a tightly synchronized manner in response to presynaptic action potentials, cholecystokinin-expressing interneurons release a variable barrage of GABA for up to several hundred milliseconds following high-frequency bursts of action potentials. The cover shows a presynaptic hippocampal basket cell (lower left) and two postsynaptic granule neurons (upper right). All three cells are filled with biocytin-Alexa488 (blue); red is immunostaining for parvalbumin, pink shows parvalbumin-positive synapses onto biocytin-filled cells. (pp 1283 and 1319)

Choosing when to seek or avoid risk can be critical for survival. McCoy and Platt report that monkeys consistently took the riskier option when asked to choose between a sure bet and a more uncertain reward, even when the risky choice led to a smaller reward on average. Neurons in the posterior cingulate cortex responded to the riskiness of these decisions. Cover illustration by Ann Thomson. (pp 1129 and 1220)

During embryonic neurogenesis, HMG-box transcription factors Sox1/2/3 suppress neural differentiation, maintaining progenitors in a proliferative state. Muhr and colleagues now demonstrate that the related transcriptional repressor Sox21 is induced by proneural transcription factors. Sox21 counteracts the activity of Sox1/2/3 and enables neuronal differentiation. The cover shows a coronal section through the spinal cord a 4 day-old chick embryo. Sox21 is labeled in red, Sox3 in green and the neuron marker NF1 in blue. (p 995)

Empathy for pain is associated with activity in brain areas important for the emotional components of pain, but do we actually feel someone else's pain? Aglioti and colleagues used transcranial magnetic stimulation to measure corticospinal excitability while subjects watched a video of a needle piercing another person's hand. The authors find reduced muscle excitability specifically in the location of the observed person's pain, suggesting a precisely localized sensorimotor component of empathy for pain. (pp 845 and 955)

Activity-dependent signaling from the synapse to the nucleus is important for synaptic plasticity and neuronal survival. David Ginty and colleagues generated conditional knockout mice for serum response factor (SRF), a candidate transcriptional regulator of activity-induced gene expression, and compared their phenotype with that of mice lacking CREB family transcription factors. CREB mutants showed neuronal degeneration, whereas the SRF mutants had synaptic plasticity deficits. Thus the authors suggest that these factors regulate distinct gene-expression programs that make differing contributions to survival and plasticity in mature neurons. (p 759)

Obesity and related metabolic disorders are on the rise worldwide. To effectively combat this new epidemic, we need a detailed understanding of the mechanisms that regulate energy intake and expenditure. In this issue we present four review articles, a perspective and a commentary highlighting current progress in the neurobiology of feeding regulation, energy metabolism and obesity. This special focus is sponsored by the Obesity Research Task Force of the National Institutes of Health. Cover image: "Venus from Willendorf," ca. 25,000-22,000 BCE. © Naturhistorisches Museum, Vienna, Austria. (pp 551-589)

As illustrated by the ballet dancers in this image, motor control involves both the maintenance of fixed positions and the ability to transition between them. However, whether or not the brain uses the same control system for posture and movement is not known. In this issue, Scott and colleagues report that individual neurons in monkey primary motor cortex represent loads differently during movement and posture tasks, suggesting specialized processes for motion and postural control. (p 498)

Elimination and strengthening of inhibitory synapses from the medial nucleus of the trapezoid body (MNTB) are essential for the formation of a precise tonotopic map in the lateral superior olive, but the mechanisms behind this plasticity are unclear. Kandler and colleagues now find that these inhibitory MNTB terminals co-release the excitatory transmitter glutamate during the period of synapse elimination, which activates postsynaptic NMDA receptors. Here, an axon terminal from a dye-filled GABA/glycinergic MNTB neuron (red) is immunolabeled against the vesicular glutamate transporter VGLUT3 (blue) and the synaptic vesicle protein SV2 (green). (pp 257 and 332)

Although the threshold for action potential initiation is lowest in the axon, the precise site of initiation is unknown. With multiple, simultaneous cell-attached recordings and immunofluorescent labeling, Häusser and colleagues find that action potentials initiate at the first node of Ranvier in cerebellar Purkinje neurons. This image shows the first node of Ranvier at the first axonal branchpoint of a Purkinje cell axon ensheathed in myelin. The axon is stained for calbindin (purple) and the myelin sheath for myelin basic protein (blue). (p 137)

Mutations in the superoxide dismutase 1 (SOD1) gene are linked to amyotrophic lateral sclerosis (ALS), a disease characterized by progressive degeneration of motoneurons. Vascular endothelial growth factor (VEGF) acts as a survival factor for motoneurons. Now Carmeliet and colleagues find that direct intra-cerebroventricular delivery of VEGF delays degeneration of spinal motoneurons and preserves neuromuscular junctions in SOD1G93A rats, an animal model of ALS. This image of a longitudinal section of a ligated rat sciatic nerve shows axonal transport of VEGF. Immunostaining labels VEGF (green) and the Schwann cell marker S100β (red), and DAPI (blue) staining labels cell nuclei. (pp 5 and 85)