This Week in The Journal
Cellular/Molecular
Neurotrophin Receptor Expression Shows Circadian Oscillation
Bernat Baeza-Raja, Kristin Eckel-Mahan, Luoying Zhang, Eirini Vagena, Igor F. Tsigelny, et al.
(see pages 10221–10234)
The neurotrophin receptor p75NTR is widely expressed in the nervous system and peripheral tissues. In neurons, p75NTR participates in axon guidance and activates apoptotic pathways; outside the nervous system, its functions include muscle and liver regeneration and angiogenesis. Having recently discovered that p75NTR is involved in glucose metabolism and insulin sensitivity, Baeza-Raja et al. hypothesized that like these processes, p75NTR expression is regulated by the circadian clock. Indeed, the p75NTR promoter contains a sequence that binds the circadian regulators Clock and Bmal1, and these transcription factors drove transcription of a p75NTR reporter in HEK293 cells. Furthermore, p75NTR levels oscillated in phase with the clock genes Per1 and Per2 in mouse suprachiasmatic nucleus (SCN, the central circadian pacemaker) and in liver, and this oscillation was disrupted in Clock-deficient mice. Interestingly, knocking out p75NTR disrupted oscillations of Per1 and Per2 in SCN and reduced expression of genes involved in glucose and lipid metabolism in liver, suggesting that p75NTR helps drive circadian oscillation of other proteins.
Development/Plasticity/Repair
SS18–CREST Exchange Allows Neuron-Specific Gene Expression
Brett T. Staahl, Jiong Tang, Wei Wu, Alfred Sun, Aaron D. Gitler, et al.
(see pages 10348–10361)
During development, cells differentiate progressively, through successive cell divisions. Phenotypic transitions result from changing transcriptional programs: one set of genes is repressed while another is activated. DNA containing repressed genes is tightly wound around histones, and switching transcriptional programs requires reorganization of this packaging, a task performed by multisubunit ATP-dependent chromatin remodeling complexes, such as BAF. Variations in BAF subunit composition across cell types underlie transcription of different sets of genes. For example, replacement of subunit BAF53a—expressed in neural progenitors—by BAF53b enables activation of neuron-specific genes as neurons exit the cell cycle. Staahl et al. report that another component of BAF complexes in embryonic stem cells and neural progenitors, SS18, is downregulated and replaced by CREST as neurons exit the cell cycle. SS18 and CREST were strongly associated with core BAF subunits, and their expression was cell type specific. Knocking down SS18 in vitro slowed stem cell proliferation, whereas forcing SS18 expression in neurons reduced CREST expression and inhibited dendritic growth.
BAF subunit SS18 is expressed specifically in neural progenitors in the ventricular zone (left), but it is replaced by the homologous subunit CREST in postmitotic neurons (right). See the article by Staahl et al. for details.
Systems/Circuits
Direct and Indirect Pathway MSNs Are Simultaneously Active
Yoshikazu Isomura, Takashi Takekawa, Rie Harukuni, Takashi Handa, Hidenori Aizawa, et al.
(see pages 10209–10220)
Two populations of medium spiny neurons (MSNs) are present in the dorsal striatum. MSNs that express D1 dopamine receptors (D1DRs) project directly to the output nuclei of the basal ganglia; their activity is enhanced by dopamine and it increases activity in downstream cortical areas. In contrast, MSNs that express D2DRs project indirectly to basal ganglia output nuclei; their activity is reduced by dopamine and decreases cortical activity. Isomura et al. compared activity patterns in these two populations as rats performed a task that involved pushing, holding (suppressing movement), then pulling a lever; every other correct performance yielded a reward. Neurons were recorded juxtacellularly, then expression of D1DRs was assessed with in situ hybridization. Surprisingly, whether a neuron was active during movement or holding, and whether its activity increased on rewarded trials, were independent of whether it expressed D1DRs: both direct and indirect-pathway MSNs were active during both movement and movement suppression, and both were positively modulated by reward expectation.
Behavioral/Cognitive
MCH Neuron Activity Induces Sleep
Roda Rani Konadhode, Dheeraj Pelluru, Carlos Blanco-Centurion, Andrew Zayachkivsky, Meng Liu, et al.
(see pages 10257–10263)
The sleep–wake cycle is controlled by antagonistic populations of wake and sleep-active neurons in the brainstem, basal forebrain, and hypothalamus. Hypothalamic neurons containing melanin-concentrating hormone (MCH) were recently found to be active during sleep, with highest activity during REM sleep, and injection of MCH into the brain increased time spent in REM sleep. To further elucidate the role of mouse MCH neurons, Konadhode et al. expressed channelrhodopsin selectively in these neurons, then optically stimulated the cells for 24 h. When stimulation began at the start of the active period (night), the latency to sleep decreased from 42 to 7 min. During the 12 h dark period, the length of individual wakefulness bouts decreased, and as a result, the total time spent awake decreased whereas time spent in REM and non-REM sleep increased. When optical stimulation began mid-day, the time spent awake and in REM or non-REM sleep were unaffected, but electroencephalographic recordings suggested sleep intensity increased. Thus, MCH neurons promote sleep.
