No abstract

Fear can be acquired vicariously through social observation of others suffering from aversive stimuli. We found that mice (observers) developed freezing behavior by observing other mice (demonstrators) receive repetitive foot shocks. Observers had higher fear responses when demonstrators were socially related to themselves, such as siblings or mating partners. Inactivation of anterior cingulate cortex (ACC) and parafascicular or mediodorsal thalamic nuclei, which comprise the medial pain system representing pain affection, substantially impaired this observational fear learning, whereas inactivation of sensory thalamic nuclei had no effect. The ACC neuronal activities were increased and synchronized with those of the lateral amygdala at theta rhythm frequency during this learning. Furthermore, an ACC-limited deletion of Ca v 1.2 Ca 2+ channels in mice impaired observational fear learning and reduced behavioral pain responses. These results demonstrate the functional involvement of the affective pain system and Ca v 1.2 channels of the ACC in observational social fear.Fear is a biological response to dangerous, threatening situations or stimuli. Fear can be acquired and expressed in a variety of ways 1 . First, fear can be learned from direct experience of an adverse situation (for example, an unconditioned stimulus in classical Pavlovian fear conditioning). In a classical conditioning experiment, pairing of a neutral, conditioned stimulus (for example, a tone) with an aversive, unconditioned stimulus (for example, a foot shock) causes an animal to express fear behaviors when the animal is later exposed to the conditioned Correspondence should be addressed to H.-S.S. (shin@kist.re.kr). 6 Present address: Department of Neurology, Seoul National University Hospital, Seoul, Korea.Note: Supplementary information is available on the Nature Neuroscience website. AUTHOR CONTRIBUTIONS COMPETING FINANCIAL INTERESTSThe authors declare no competing financial interests.Reprints and permissions information is available online at http://www.nature.com/reprintsandpermissions/. 1,[6][7][8][9][10][11][12] . Previous studies using a barpressing protocol found that rats seeing a distressed conspecific (by electric shocks) display fearful behavioral responses, such as crouching or motionlessness 13,14 . A recent study found that C57BL/6J mice that observed unfamiliar mice experiencing classical fear conditioning displayed freezing behaviors when they were later exposed to the conditioned stimulus alone 15 . These findings demonstrate social transfer of fear in rodents. Unlike classical fear conditioning, however, the neural substrate and mechanism underlying observational social fear has not been well defined. NIH Public AccessACC is known to receive sensory signals from the somatosensory cortices and other cortical areas, including the anterior insular cortex [16][17][18][19][20] . Brain-imaging studies in humans have shown that the neuronal activities of the ACC and the amygdala change during observation of others experi...

The polyoma virus middle-T and the T24 Harvey ras1 genes are individually unable to transform primary baby rat kidney cells. Adenovirus early region 1A provides functions required by these genes to transform primary cells following DNA-mediated gene transfer. These results suggest that separate establishment and transforming functions are required for oncogenic transformation of primary cells in culture.

Oncogenic transformation by human adenoviruses requires early regions 1A and 1B (E1A and EIB) and provides a model of multistep carcinogenesis. This study shows that the metabolic stabilization of p53 observed in adenovirus 5 (Ad5)-transformed cells can occur in untransformed cells expressing E1A alone. Stabilized p53 was localized to the nucleus and was indistinguishable from wild-type p53 with respect to its interactions with hsc70, PAb420, AdS p55 E~s, and SV40 large T antigen. Moreover, binding of AdS p55 ~B or SV40 large T antigen had no additional effect on p53 levels or turnover. Higher levels of p53 were also induced in a variety of cell types within 40 hr after transferring E1A genes. E1A also caused cells to lose viability by a process resembling apoptosis. The apoptosis appeared to involve p53, because p53 levels reverted to normal in surviving cells that had lost E1A, and E1B protected cells from the toxic effects of E1A. These results suggest that (1) the involvement of p53 in tumor suppression and/or apoptosis can be regulated at the level of protein turnover, and (2) a major oncogenic role for E1B is to counter cellular responses to E1A (i.e., stabilization of p53 and associated apoptosis) that preclude transformation by EIA alone. This represents the first physiological setting in which high levels of endogenous p53 are induced in response to an oncogenic challenge, with the apparent consequence of suppressing transformation.

Protein arginine N-methyltransferases have been implicated in a variety of processes, including cell proliferation, signal transduction, and protein trafficking. In this study, we have characterized essentially a null mutation induced by insertion of the U3␤Geo gene trap retrovirus into the second intron of the mouse protein arginine N-methyltransferase 1 gene (Prmt1). cDNAs encoding two forms of Prmt1 were characterized, and the predicted protein sequences were found to be highly conserved among vertebrates. Expression of the Prmt1-␤geo fusion gene was greatest along the midline of the neural plate and in the forming head fold from embryonic day 7.5 (E7.5) to E8.5 and in the developing central nervous system from E8.5 to E13.5. Homozygous mutant embryos failed to develop beyond E6.5, a phenotype consistent with a fundamental role in cellular metabolism. However, Prmt1 was not required for cell viability, as the protein was not detected in embryonic stem (ES) cell lines established from mutant blastocysts. Low levels of Prmt1 transcripts (approximately 1% of the wild-type level) were detected as assessed by a quantitative reverse transcription-PCR assay. Total levels of arginine N-methyltransferase activity and asymmetric N G ,N G -dimethylarginine were reduced by 85 and 54%, respectively, while levels of hypomethylated substrates were increased 15-fold. Prmt1 appears to be a major type I enzyme in ES cells, and in wild-type cells, most substrates of the enzyme appear to be maintained in a fully methylated state.Methylation of arginine residues is one of many covalent modifications of eukaryotic proteins that occur concomitant with or shortly following translation. Two types of protein arginine methyltransferases have been classified according to their substrate specificity and reaction products (reviewed in reference 11). Type I enzymes catalyze the formation of N G -monomethylarginine and asymmetric N G ,N G -dimethylarginine, while type II enzymes catalyze the formation of N Gmonomethylarginine and symmetric N G ,NЈ G -dimethylarginine. Most substrates for type I enzymes bind nucleic acid, usually RNA. These include heterogeneous nuclear RNA binding proteins (hnRNPs), which collectively contain 65% of the nuclear asymmetric dimethylarginine, as well as fibrillarin and nucleolin (19-21). The only known physiological substrate of symmetric (type II) arginine methyltransferase is myelin basic protein, a major protein component of the myelin sheath.Genes encoding rat (PRMT1), human (HRMT1L2), and yeast (RMT1) type I enzymes have been characterized (12,13,17,29). The mammalian genes appear to be ubiquitously expressed in all tissues (17, 29, 32). The yeast enzyme, which is not required for cell viability, accounts for over 85% of the protein dimethylarginine in the cell (12).Type I enzymes have been implicated in a variety of processes, including cell growth control, signal transduction, and protein trafficking, but the biochemical and biological functions of arginine methylation have not been established. The enz...