Cellular/Molecular
Potassium May Link Neural Activity to Glycolysis
Carla X. Bittner, Rocío Valdebenito, Iván Ruminot, Anitsi Loaiza, Valeria Larenas, et al.
(see pages 4709–4713)
Synaptic activity consumes much energy and is tightly coupled to increases in glucose metabolism, resulting in a surge of lactate release within seconds of neuronal activation. Much activity-associated glycolysis occurs in astrocytes and is thought to be stimulated indirectly by glutamate released during synaptic transmission: glutamate is transported into astrocytes along with Na+, elevated intracellular Na+ stimulates the Na+/K+ ATPase, and the latter promotes glycolysis. Bittner et al. tested this hypothesis by using fluorescence resonance energy transfer to measure glucose and glycolytic rate in mouse hippocampal astrocytes. Although increasing extracellular glutamate increased astrocytic glycolysis and lactate release, the time course was slow, requiring several minutes. Increasing intracellular Na+ concentration increased glycolysis over a similar time course. In contrast, K+ increased astrocytic glycolysis and lactate release within seconds. Blocking the Na+/K+ ATPase prevented the K+-induced increase in glycolysis, suggesting that K+ released during synaptic transmission couples neuronal activity to glucose utilization.
Development/Plasticity/Repair
Grafted Progenitors Relay Sensory Information Through Lesion
Joseph F. Bonner, Theresa M. Connors, William F. Silverman, David P. Kowalski, Michel A. Lemay, et al.
(see pages 4675–4686)
Despite decades of promising advances, restoring connectivity after spinal cord injury has had limited success. Major obstacles include downregulation of growth-promoting molecules in adult spinal cord, inability of mature axons to sustain extended growth, prevention of growth by scar tissue, and inflammation that triggers degeneration of fibers spared by the initial injury. A multipronged approach is required to overcome these obstacles. Bonner et al. grafted neural progenitors, which differentiate and can extend axons, and glial-restricted progenitors, which create a growth-friendly environment, into transected dorsal columns of rats. They then virally expressed brain-derived neurotrophic factor in dorsal column nuclei (DCN) to guide grafted progenitors' axons. Severed sensory axons grew into grafts and formed functional synapses with graft neurons. Graft neurons extended axons and synapsed onto host DCN neurons, although few of these synapses appeared fully functional. Nonetheless, the procedure restored sensory-evoked electrical activity in the DCN, indicating that with modification, this approach might restore function.
Behavioral/Systems/Cognitive
Reward Sensitivity May Be Elevated Before Onset of Obesity
Eric Stice, Sonja Yokum, Kyle S. Burger, Leonard H. Epstein, and Dana M. Small
(see pages 4360–4366)
Food consumption is primarily regulated by hormones related to energy balance, but palatable foods that activate reward circuitry can also stimulate eating. Improper functioning of either energy-regulating or reward circuitry can cause excessive eating and thus lead to obesity. What impairments in reward processing contribute to obesity remain unclear, however. Some evidence suggests that obese individuals are hypersensitive to hedonic properties of food, and overeat because eating is especially enjoyable. Contrasting evidence suggests that obese people are hyposensitive to reward, and therefore eat more than others to achieve similar levels of satisfaction. But overeating reduces reward sensitivity, confounding studies of reward processing in obese subjects. Therefore, Stice et al. imaged brain activity in normal-weight adolescents who were at risk of becoming obese, based on parental obesity. Activation of reward-related brain areas was greater in high-risk subjects than in controls during receipt of palatable food or money, suggesting that reward sensitivity is elevated in people at risk of becoming obese.
Neurobiology of Disease
NPC1 Expression Is Required Cell-Autonomously for Neuron Survival
Manuel E. Lopez, Andres D. Klein, Ubah J. Dimbil, and Matthew P. Scott
(see pages 4367–4378)
Niemann-Pick disease type C (NP-C) results from impaired processing of cholesterol, leading to accumulation of lipids in lysosomes throughout the body. NP-C is usually caused by mutation of NPC1, a ubiquitously expressed gene whose precise function is unclear. Clinical manifestations of NP-C vary greatly and include both visceral and brain pathology, but the latter is more severe, ultimately resulting in neurodegeneration and death. Cholesterol is a major component of myelin, but it is also essential for neuronal functions, including synaptogenesis. Because cholesterol does not cross the blood–brain barrier, it is synthesized locally, by astrocytes. Therefore, neurological effects in NP-C could stem from abnormal cholesterol processing in neurons or glia. To study these possibilities, Lopez et al. expressed wild-type NPC1 in specific cell types in otherwise NPC1-null mice. Neuron-specific expression cell-autonomously reduced cholesterol accumulation, reduced local reactive gliosis, and extended survival. In contrast, astrocyte-specific expression had minimal impact on neuropathology or disease progression.