Noah E. Letwin, Neri Kafkafi, Yoav Benjamini, Cheryl Mayo, Bryan C. Frank, Troung Luu, Norman H. Lee, and Greg I. Elmer
This week, Letwin et al. began a search for genes that underlie complex behaviors, eschewing the conventional hunt for individual genes in favor of a behavioral genetics approach. They fabricated microarrays containing >26,000 mouse cDNAs. Gene expression patterns were measured across five brain regions--the prefrontal cortex, ventral striatum, temporal lobe, periaqueductal gray, and cerebellum--and across eight inbred strains of mice that are considered genetically and behaviorally diverse. By the authors' criteria, each region had hundreds (range, 245–1251) of regionally enriched genes that were conserved across strains. Roughly similar numbers of genes differed in each region between strains. In parallel, they compared behavioral phenotypes for anxiety, locomotor activity, ethanol-induced locomotor activity, and seizure susceptibility, and tried to link the regional expression differences with behavioral phenotypes. Some of the genes that correlated with behaviors were linked to already established quantitative trait loci, thus validating the potential utility of this daunting task.
2. Small Molecule p75NTR Ligands
Stephen M. Massa, Youmei Xie, Tao Yang, Anthony W. Harrington, Mi Lyang Kim, Sung Ok Yoon, Rosemary Kraemer, Laura A. Moore, Barbara L. Hempstead, and Frank M. Longo
The neurotrophin receptor p75NTR is a bit of a chameleon, leading to apoptosis or cell survival, depending on the activating ligand and on the expression of tropomyosin-related kinase (Trk) neurotrophin receptors. Binding of nerve growth factor (NGF) to p75NTR promotes neuron survival, whereas proNGF induces cell death, as does the unbound monomeric p75NTR. In this issue, Massa et al. report on several small nonpeptide ligands that bind p75NTR. The authors used virtual, or in silico, screening to identify compounds similar to NGF â-hairpin loop 1. Four loop 1 mimic (LM11A) compounds had neurotrophic, prosurvival activity in cultured mouse hippocampal neurons. Several criteria supported their action as ligands for monomeric p75NTR. Specifically, the compounds did not promote survival of p75NTR−/− neurons, and they competed with NGF for binding to p75NTR-Fc but not TrkA-Fc. The LM11A compounds also displaced a p75NTR antibody targeted to the neurotrophinbinding domain, and they activated signaling molecules downstream of p75NTR.
3. Nociceptor Stimulation and the fMRI
Belinda Susanne Ruehle, Hermann Otto Handwerker, Jochen Klaus Maria Lennerz, and Ralf Ringler
Ruehle et al. used functional magnetic resonance imaging (fMRI) in 13 willing human subjects to visualize the brain regions that contribute to acute pain versus inflammatory pain and hyperalgesia. Nociceptive sensory neurons, or C-fibers, can be subdivided into polymodal mechano-heat-responsive units (CMH) that respond to mechanical and thermal stimuli, and mechano-insensitive units (CMi) that become sensitive to mechanical stimuli only after inflammation. The authors used low-intensity transcutaneous stimulation (TCS) to selectively activate CMH nociceptors, and stronger intracutaneous stimulation (ICS) to activate CMi neurons. The subjects described TCS-induced pain as "stinging" and ICS-induced pain as "deep," "pounding," or "dull". All subjects found one or both unpleasant. Both stimuli activated known pain-processing brain areas, but each stimulus also activated distinct areas. TCS activated nocifensive motor response centers necessary for an immediate withdrawal response, whereas only ICS increased activity in the posterior cingulate cortex thought to be involved in pain memory and aversion.
4. Corticosteroids and Rat Neural Stem Cells
Maria Sundberg, Suvi Savola, Anni Hienola, Laura Korhonen, and Dan Lindholm
In this week's Journal, Sundberg et al. examined potential links between stress, steroids, and stem cells. The authors reported that neuronal stem cells (NSCs) isolated from embryonic rat brains expressed glucocorticoid receptors (GRs) and mineralocorticoid receptors. The potent synthetic glucocorticoid dexamethasone (Dex) also decreased NSC proliferation in vivo. A 3 d treatment of embryonic day 14 pregnant rats reduced NSCs in the pups by one-third, an effect attributed to decreased proliferation rather than increased cell death. The authors estimated that the treatment half-saturated glucocorticoid receptors, making it plausible that the effects could occur under physiological conditions. In vitro, Dex activation of GRs increased activity of the ubiquitin proteasome system but not the glycogen synthase kinase-â signaling pathway, both of which regulate the cell cycle protein cyclin D1. Dex increased the ubiquitination of cyclin D1, thereby targeting it for degradation and blunting its proliferative effects. Overexpression of cyclin D1 increased NSC proliferation and offset the effect of Dex.