Patterns of responding differentiate intravenous nicotine self-administration from responding for a visual stimulus in C57BL/6J mice

Testing genetically engineered mice in a reliable nicotine self-administration procedure could provide important insights into the molecular mechanisms underlying nicotine reinforcement. We assessed operant responding for intravenous nicotine infusions in C57BL/6J male mice under a fixed-ratio 3 schedule of reinforcement in which a visual cue was contingently associated with drug delivery. Acquisition, dose-response function, extinction, and cue-induced reinstatement of operant behavior were characterized. Low nicotine doses (0.001-0.06 mg/kg/infusion) elicited response rates similar to those supported by saline, whereas a higher dose (0.1 mg/kg/infusion) decreased responding. Using an identical procedure to assess cocaine self-administration in an independent group of mice yielded an inverted U-shaped dose-response curve. Other mice trained to respond exclusively for the visual stimulus earned a similar number of reinforcers as mice self-administering saline or low nicotine doses, although with a lower selectivity for the active lever and their response rates were sensitive to the discontinuation and resumption of cue light presentation. Finally, patterns of responding for nicotine, cocaine, or the visual stimulus alone were analyzed using frequency distributions of inter-response intervals and extended return maps. These analyses revealed unique properties of nicotine, which dose-dependently delayed the first response post-timeout and increased the regularity of lever pressing activity. Nicotine did not enhance the reinforcing properties of the visual cue paired with drug delivery. Interestingly, however, patterns of responding could differentiate nicotine self-administration from responding for a visual stimulus or saline and indicated that nicotine functioned as a salient stimulus driving highly regular operant behavior

Supersymmetric Self-Gravitating Solitons

We show that the `instantonic' soliton of five-dimensional Yang-Mills theory and the closely related BPS monopole of four-dimensional Yang-Mills/Higgs theory continue to be exact static, and stable, solutions of these field theories even after the inclusion of gravitational, electromagnetic and, in the four-dimensional case, dilatonic interactions, provided that certain non-minimal interactions are included. With the inclusion of these interactions, which would be required by supersymmetry, these exact self-gravitating solitons saturate a gravitational version of the Bogomol'nyi bound on the energy of an arbitrary field configuration.Comment: 39 pages, DAMTP R-93/27, phyzz

Dynamic transcriptomic analysis reveals suppression of PGC1α/ERRα drives perturbed myogenesis in facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is a prevalent, incurable myopathy, linked to epigenetic de-repression of D4Z4 repeats on chromosome 4q, leading to ectopic DUX4 expression. FSHD patient myoblasts have defective myogenic differentiation, forming smaller myotubes with reduced myosin content. However, molecular mechanisms driving such disrupted myogenesis in FSHD are poorly understood. We performed high-throughput morphological analysis describing FSHD and control myogenesis, revealing altered myogenic differentiation results in hypotrophic myotubes. Employing polynomial models and an empirical Bayes approach, we established eight critical time-points during which human healthy and FSHD myogenesis differ. RNA-sequencing at these eight nodal time-points in triplicate, provided temporal depth for a multivariate regression analysis, allowing assessment of interaction between progression of differentiation and FSHD disease status. Importantly, the unique size and structure of our data permitted identification of many novel FSHD pathomechanisms undetectable by previous approaches. Selected for further analysis here, were pathways that control mitochondria: of interest considering known alterations in mitochondrial structure and function in FSHD muscle, and sensitivity of FSHD cells to oxidative stress. Notably, we identified suppression of mitochondrial biogenesis, in particular via PGC1α, the co-factor and activator of ERRα. PGC1α knock-down caused hypotrophic myotubes to form from healthy myoblasts. Known ERRα agonists and safe food supplements Biochanin A, Genistein or Daidzein, each rescued the hypotrophic FSHD myotube phenotype. Together our work describes transcriptomic changes in high resolution that occur during myogenesis in FSHD ex-vivo, identifying suppression of the PGC1α-ERRα axis leading to perturbed myogenic differentiation, which can effectively be rescued by readily-available food supplements

Amygdala 14-3-3ζ as a Novel Modulator of Escalating Alcohol Intake in Mice

Alcoholism is a devastating brain disorder that affects millions of people worldwide. The development of alcoholism is caused by alcohol-induced maladaptive changes in neural circuits involved in emotions, motivation, and decision-making. Because of its involvement in these processes, the amygdala is thought to be a key neural structure involved in alcohol addiction. However, the molecular mechanisms that govern the development of alcoholism are incompletely understood. We have previously shown that in a limited access choice paradigm, C57BL/6J mice progressively escalate their alcohol intake and display important behavioral characteristic of alcohol addiction, in that they become insensitive to quinine-induced adulteration of alcohol. This study used the limited access choice paradigm to study gene expression changes in the amygdala during the escalation to high alcohol consumption in C57BL/6J mice. Microarray analysis revealed that changes in gene expression occurred predominantly after one week, i.e. during the initial escalation of alcohol intake. One gene that stood out from our analysis was the adapter protein 14-3-3ζ, which was up-regulated during the transition from low to high alcohol intake. Independent qPCR analysis confirmed the up-regulation of amygdala 14-3-3ζ during the escalation of alcohol intake. Subsequently, we found that local knockdown of 14-3-3ζ in the amygdala, using RNA interference, dramatically augmented alcohol intake. In addition, knockdown of amygdala 14-3-3ζ promoted the development of inflexible alcohol drinking, as apparent from insensitivity to quinine adulteration of alcohol. This study identifies amygdala 14-3-3ζ as a novel key modulator that is engaged during escalation of alcohol use

Comparative genetic analysis: the utility of mouse genetic systems for studying human monogenic disease

One of the long-term goals of mutagenesis programs in the mouse has been to generate mutant lines to facilitate the functional study of every mammalian gene. With a combination of complementary genetic approaches and advances in technology, this aim is slowly becoming a reality. One of the most important features of this strategy is the ability to identify and compare a number of mutations in the same gene, an allelic series. With the advent of gene-driven screening of mutant archives, the search for a specific series of interest is now a practical option. This review focuses on the analysis of multiple mutations from chemical mutagenesis projects in a wide variety of genes and the valuable functional information that has been obtained from these studies. Although gene knockouts and transgenics will continue to be an important resource to ascertain gene function, with a significant proportion of human diseases caused by point mutations, identifying an allelic series is becoming an equally efficient route to generating clinically relevant and functionally important mouse models

MtNramp1 mediates iron import in rhizobia-infected Medicago truncatula cells.

Symbiotic nitrogen fixation is a process that requires relatively high quantities of iron provided by the host legume. Using synchrotron-based X-ray fluorescence, we have determined that this iron is released from the vasculature into the apoplast of zone II of M. truncatula nodules. This overlaps with the distribution of MtNramp1, a plasma membrane iron importer. The importance of MtNramp1 in iron transport for nitrogen fixation is indicated by the 60% reduction of nitrogenase activity observed in knock-down lines, most likely due to deficient incorporation of this essential metal cofactor at the necessary levels

Faster is not surer--a comparison of C57BL/6J and 129S2/Sv mouse strains in the watermaze.

In recent years the use of genetic manipulations to investigate the molecular mechanisms underlying learning and memory has become a common approach. In a great many cases, the spatial learning ability of mutant mice has been assessed using the Morris watermaze task. The performance of these mice may, however, be strongly influenced by their genetic background and, therefore, the interpretation of their phenotype requires a preliminary characterization of the parental strains. The present study compared 129S2/Sv and C57/BL/6J inbred mouse strains, which have been widely used in deriving lines of genetically modified mice, on the hidden platform version of the watermaze task. During acquisition, the C57 mice displayed shorter escape latencies to find the platform than the 129S2s. Further analysis revealed, however, that the C57 mice also swam faster than the 129S2s. The analysis of path lengths was thus a more reliable measure of spatial learning, and revealed an equal level of performance in the two strains. This conclusion was confirmed during the two probe trials with both strains showing a similar spatial preference for the training site. These results suggest that the 129S2 substrain is no less proficient than the C57 substrain in terms of spatial learning in the watermaze, and also demonstrates the importance of not relying solely on escape latency as a measure of watermaze performance

BK Channels in the Vertebrate Inner Ear

The perception of complex acoustic stimuli begins with the deconstruction of sound into its frequency components. This spectral processing occurs first and foremost in the inner ear. In vertebrates, two very different strategies of frequency analysis have evolved. In nonmammalian vertebrates, the sensory hair cells of the inner ear are intrinsically electrically tuned to a narrow band of acoustic frequencies. This electrical tuning relies on the interplay between BK channels and voltage-gated calcium channels. Systematic variations in BK channel density and kinetics establish a gradient in electrical resonance that enables the coding of a broad range of acoustic frequencies. In contrast, mammalian hair cells are extrinsically tuned by mechanical properties of the cochlear duct. Even so, mammalian hair cells also express BK channels. These BK channels play critical roles in various aspects of mammalian auditory signaling, from developmental maturation to protection against acoustic trauma. This review summarizes the anatomical localization, biophysical properties, and functional contributions of BK channels in vertebrate inner ears. Areas of future research, based on an updated understanding of the biology of both BK channels and the inner ear, are also highlighted. Investigation of BK channels in the inner ear continues to provide fertile research grounds for examining both BK channel biophysics and the molecular mechanisms underlying signal processing in the auditory periphery

Autres communications (résumés)

Sournia Jean-Charles, Troupeau G., Le Coz R., Roux-Dessarps M., Samion-Contet J. Autres communications (résumés). In: Revue d'histoire de la pharmacie, 86ᵉ année, n°317, 1998. pp. 49-50