Cellular/Molecular
Methylene Blue May Slow Huntington's Disease
Emily Mitchell Sontag, Gregor P. Lotz, Namita Agrawal, Andrew Tran, Rebecca Aron, et al.
(see pages 11109–11119)
Methylene blue (MB) was developed as a textile dye in the late 19th century, but it was found to be better for staining tissues—especially nervous tissue—than for fabrics. The reduced form of MB is lipophilic and easily crosses cell membranes, but inside cells it becomes oxidized and forms a blue precipitate. Because the oxidized and reduced forms are in equilibrium, MB can act as either a peroxidant or antioxidant. Its numerous biological effects include inactivating microbes; inhibiting soluble guanylate cyclase, nitric oxide synthase, and acetylcholinesterase; and modulating membrane transporters and ion channels. Through these and/or other mechanisms, MB can enhance memory and treat psychoses, depression, and possibly Alzheimer's disease. Sontag et al. report that MB might also be useful in treating Huntington's disease (HD). In a mouse HD model, MB slowed the progression of sensorimotor impairment, possibly by reducing aggregation of huntingtin protein or by increasing levels of brain-derived neurotrophic factor.
Development/Plasticity/Repair
Neurons Become Active Early in ENS Development
Marlene M. Hao, Alan E. Lomax, Sonja J. McKeown, Christopher A. Reid, Heather M. Young, et al.
(see pages 10949–10960)
The enteric nervous system (ENS), which lies within the walls of the gut, is essential for normal peristalsis. Although it receives CNS input, the ENS is independently necessary and sufficient to generate gut movements. Malformation of the ENS leads to fatal intestinal blockage. The ENS derives from the neural crest, and precursors proliferate and differentiate as they migrate caudally and invade the gut. Approximately 20 subtypes of ENS neurons have been identified, as have many genes that regulate precursor proliferation and differentiation. Still, little is known about the functional development of the ENS. Therefore, Hao et al. examined the development of ENS excitability in embryonic mice. Neural markers were expressed before excitable properties were acquired, and the first active property to appear was graded responses to depolarization, which was mediated by an unidentified voltage-gated inward current. Spiking commenced later, after enough voltage-gated Na+ channels were expressed. Finally, conductances underlying slow afterhyperpolarization emerged perinatally.
Behavioral/Systems/Cognitive
Cerebo-ponto-cerebellar Projections Do Not Adhere to Zones
Lucia Suzuki, Patrice Coulon, Erika H. Sabel-Goedknegt, and Tom J. H. Ruigrok
(see pages 10854–10869)
Cerebellar output is organized as modules comprising longitudinal zones of Purkinje cells that project to different cerebellar nuclei. Each zone receives input from a particular subnucleus of the inferior olive. Relatively little is known about the more complex organization of inputs to the cerebellum from the cerebral cortex via pontine nuclei, however. Suzuki et al. examined this circuitry by coinjecting cholera toxin (CT) and rabies virus (RV) into rat cerebellar cortex. Transsynaptic retrograde transport of RV identified second-order projections from cerebral cortex, while retrograde transport of CT labeled olivary neurons, thus enabling identification of the injected zone(s). Cerebro-ponto-cerebellar projections did not adhere strongly to the zonal organization. Instead, neurons projecting to different zones within a given lobule were largely intermixed in the pons and cerebral cortex. Interestingly, projections to the vermis of lobule VII originated in widespread cortical regions, including retrosplenial and orbitofrontal cortices, supporting a role for this lobule in nonmotor functions.
RV injected into the vermis of cerebellar lobule VII labeled neurons (yellow dots) in wide regions of the cerebral cortex. See the article by Suzuki et al. for details.
Neurobiology of Disease
Reactive Astrocytes May Promote HIV-Related Pain
Yuqiang Shi, Benjamin B. Gelman, Joshua G. Lisinicchia, and Shao-Jun Tang
(see pages 10833–10840)
Intense or prolonged activation of nociceptor afferents—which occurs, for example, after peripheral nerve injury—sensitizes central nociception pathways, resulting in chronic pain. In animal models, spinal dorsal horn microglia and astrocytes contribute to the development and maintenance of chronic pain by secreting proinflammatory cytokines. Evidence for glial contributions to chronic pain in humans has been lacking, however. Shi et al. obtained such evidence by examining postmortem dorsal horn tissue from HIV-infected patients. Many, but not all HIV patients develop chronic pain. Markers of reactive astrocytes were expressed at higher levels in patients who had experienced chronic pain than in patients and uninfected controls who had not. The number of reactive astrocytes was also increased in pain-positive patients, as were the levels of proinflammatory cytokines. In contrast, two markers of reactive microglia were not significantly different between pain and pain-free patients, suggesting these cells are not required to maintain HIV-associated pain.
