Disagreeable, Villainous, and Wimpy: The Child as Antihero in Burnett, Colfer, and Kinney

Although children’s literature is often dismissed as largely didactic and supportive of entrenched power structures, an examination of the antihero’s development in children’s literature reveals the genre’s complexity and subtle challenges of social mores. Critics focus extensive attention on the redemption of a less-than-ideal character from social deviancy to normalcy in fiction for young readers, but more rarely do they discuss those characters that remain static in their lack of heroic qualities and fail as role models for children. The on-going discussion on conventional subgenres like the school story does not often include texts that subvert the form with bullying or “wimpy” protagonists. Most significantly, the debate over the role of children’s literature in maintaining or questioning adult authority often passes over books that show children committing immoral actions usually reserved for adults. In the following pages, I place the ironic mode and the antihero into the context of literature for children, focusing primarily on a close reading of three texts from British and American writers in the twentieth and twenty-first centuries: The Secret Garden by Frances Hodgson Burnett, Artemis Fowl by Eoin Colfer, and Diary of a Wimpy Kid by Jeff Kinney. Each of the protagonists will be examined in light of the cultural contexts of the writers, the overall messages of the books, and the stories’ relationships to existing genre conventions. My research draws conclusions about when the child antihero emerges in literary history, how the antihero helps communicate the writer’s message about a particular issue or society in general, and why a writer chooses for the antihero to find redemption or not. Together, the three novels provide a fascinating look at how children’s novels depart from tradition yet remain very much a part of a literary canon

Hypoinsulinemia Regulates Amphetamine-Induced Reverse Transport of Dopamine

The behavioral effects of psychomotor stimulants such as amphetamine (AMPH) arise from their ability to elicit increases in extracellular dopamine (DA). These AMPH-induced increases are achieved by DA transporter (DAT)-mediated transmitter efflux. Recently, we have shown that AMPH self-administration is reduced in rats that have been depleted of insulin with the diabetogenic agent streptozotocin (STZ). In vitro studies suggest that hypoinsulinemia may regulate the actions of AMPH by inhibiting the insulin downstream effectors phosphotidylinositol 3-kinase (PI3K) and protein kinase B (PKB, or Akt), which we have previously shown are able to fine-tune DAT cell-surface expression. Here, we demonstrate that striatal Akt function, as well as DAT cell-surface expression, are significantly reduced by STZ. In addition, our data show that the release of DA, determined by high-speed chronoamperometry (HSCA) in the striatum, in response to AMPH, is severely impaired in these insulin-deficient rats. Importantly, selective inhibition of PI3K with LY294002 within the striatum results in a profound reduction in the subsequent potential for AMPH to evoke DA efflux. Consistent with our biochemical and in vivo electrochemical data, findings from functional magnetic resonance imaging experiments reveal that the ability of AMPH to elicit positive blood oxygen level–dependent signal changes in the striatum is significantly blunted in STZ-treated rats. Finally, local infusion of insulin into the striatum of STZ-treated animals significantly recovers the ability of AMPH to stimulate DA release as measured by high-speed chronoamperometry. The present studies establish that PI3K signaling regulates the neurochemical actions of AMPH-like psychomotor stimulants. These data suggest that insulin signaling pathways may represent a novel mechanism for regulating DA transmission, one which may be targeted for the treatment of AMPH abuse and potentially other dopaminergic disorders

STZ Decreases Akt Activity in Rat Striatum

<div><p>(A) Representative immunoblots for phosphorylated GSK3α (pGSK3α), a downstream target of Akt, in either untreated subjects (control) or in those that received STZ 1 wk before sacrificing the animals.</p> <p>(B) Quantitation of pGSK3α immunoreactivity conducted in striatal synaptosomes 7 d after STZ (65 mg/kg, intravenous [i.v.]). The densities of the <i>p</i>GSK3α bands were normalized to their respective total protein concentrations (determined by protein assay; 100 μg) and then expressed as a percentage of control. *<i>p</i> < 0.05, paired Students <i>t</i>-test (<i>n</i> = 3).</p></div

Cell Surface DAT Expression within Striatum Is Reduced in STZ-Treated Rats

<p>(A) Representative immunoblots for biotinylated (surface) and total DAT, in either untreated subjects (control) or in those that received streptozotocin (STZ). (B) Quantitation of DAT immunoreactivity from immunoblotting as in panel A conducted in striatal synaptosomes 7 d after STZ (65 mg/kg, i.v.). Biotinylated proteins (30 μg), representing 10% of the total lysate (300 μg protein) were separated by SDS-PAGE and underwent immunoblotting with a DAT-specific antibody; samples containing total lysates were run on adjacent lanes. Each biotinylated DAT band density was normalized to that of its corresponding total DAT band. Surface-to-total DAT ratios were then expressed as a percentage of control. *<i>p</i> < 0.05, Students <i>t</i>-test for independent samples (<i>n</i> = 3).</p

Depletion of Insulin Severely Blunts the Ability of AMPH to Release DA

<div><p>(A) Shown in the figure are integrated DA oxidation traces from a representative control rat and a STZ-treated rat, obtained using HSCA in the striatum. AMPH (400 μM/125 nl) was microinjected into the striatum (arrow), and extracellular DA levels were measured.</p> <p>(B–D) Summary data for HSCA, *<i>p</i> < 0.05, Students <i>t</i>-test for independent samples (<i>n</i> = 6). The slope of the rising portion of the DA signal—indicating the rate of AMPH-induced DA release—was decreased in STZ-treated rats compared to control (B), as was the amount of released DA (C). The slope of the descending phase of the DA signal, corresponding to the rate of clearance of AMPH-evoked DA, was also diminished in hypoinsulinemic rats (D).</p></div

Local Infusion of Insulin Restores AMPH-Evoked DA Release in Striatum of STZ-Treated Rats

<p>Summary data for HSCA (<i>n</i> = 5–7). When measured in the dorsal striatum and compared to saline-treated control subjects, STZ-induced depletion of insulin (STZ) resulted in a significant reduction in the rate of DA efflux in response to local injection of AMPH (400 μM/125 nl; (A) as well as a decrease in the maximum amount of released DA (B) and the rate of DA clearance (C) with respect to control. These findings provide a replication of those shown in <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0050274#pbio-0050274-g002" target="_blank">Figure 2</a> in a separate cohort of rats. In contrast, when exogenous insulin (10 μM/100 nl) is locally applied in STZ animals 2 min prior to AMPH (STZ+Ins), all three of these electrochemical parameters are normalized to levels approximating control. One-way ANOVA (<i>F</i>_2,14 = 2.46; <i>p</i> < 0.05); Mann-Whitney (<i>p</i> < 0.05 compared to Control* and STZ+Ins#).</p

Inhibition of PI3K Decreases AMPH-Induced Striatal DA Release

<p>DA concentration was determined by digital integration of in vitro–calibrated oxidative currents using HSCA recordings in the striatum. The PI3K inhibitor LY294002 or vehicle (aCSF in DMSO) was microinjected into the striatum 300 μm away from the carbon fiber electrode. AMPH (400 μM/125 nl) was then ejected 0, 45 or 90 min later. Data represent peak AMPH-induced DA release expressed as a percentage of vehicle. Main effect treatment <i>p</i> < 0.005, two-way ANOVA; *<i>p</i> < 0.05, Bonferroni post hoc (<i>n</i> = 3–4).</p

AMPH-Induced Striatal BOLD fMRI Responses Are Attenuated in STZ-Treated Rats

<div><p>(A) <i>t</i>-thresholded statistical maps (<i>p</i> < ±0.05 to <i>p</i> < ±0.0001; uncorrected comparisons of 15-min baseline period versus 15-min post-injection period) were constructed from subjects that best represent the BOLD signal activation within the DAT- and IR-enriched dorsal striatum. BOLD signal changes in response to saline (left panels) versus acute AMPH (right panels) within untreated control rats (top panels) versus STZ-treated rats (bottom panels). Compared to drug-naive animals given saline, AMPH [3 mg/kg, i.p.] elicited considerable BOLD activation in the dorsal striatum. This response was absent in drug-naive, STZ-pretreated hypoinsulinemic rats (arrow).</p> <p>(B) ROI analyses of striatal BOLD fMRI data for all subjects individually for each of the four treatment conditions in Panel A (<i>n</i> = 5–6).</p> <p>(C) Integration of fMRI time series data reveals significant group differences in BOLD activation within the dorsal striatal ROIs. One-way ANOVA (<i>F</i>_7,56 = 2.83, <i>p</i> < 0.05); Newman-Keuls (<i>p</i> < 0.05 compared to Baseline*, Saline+ and Control#).</p> <p>(D) Three-dimensional stereotaxic orientation of the striatal ROIs (1.88 × 1.88 × 1 mm) analyzed in (B and C). Shown at the bottom of each slice—representing axial, sagittal and coronal orientations—are the corresponding stereotaxic coordinates for the ROIs [<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0050274#pbio-0050274-b068" target="_blank">68</a>].</p></div